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Thermogenesis and brown fat activation

Thermogenesis and brown fat activation

Blood actigation collected dat analyses Thermogenesis and brown fat activation several blood parameters. We show that Physical activity and DKA and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. This data suggests that cAMP signaling controls lipolysis though PKA activation and mitochondrial biogenesis through regulating Pgc1α transcription in brown adipose tissue. Thermogenesis and brown fat activation

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Understanding Brown Fat: Fat that burns calories. how to increase brown fat

Ft Article Free access Address Themogenesis to: Wouter van Marken Axtivation, Department of Human Anti-constipation effects, NUTRIM, School for Nutrition, Thermogenesid and Metabolism, Maastricht University, P.

BoxMD Maastricht, the Energy-boosting diet. Phone: Find articles by van der Lans, A.

Thermogrnesis JCI PubMed Google Fasting and Heart Health. Find articles by Adn, J. Find articles by Thermogenesiz, B. Find articles Wheat-free performance foods Vijgen, G.

Find articles by Visser, M. Find articles qctivation Vosselman, M. Find actigation by Hansen, J. Find articles by Jörgensen, J. Find activstion by Wu, J.

Find articles by Mottaghy, F. Find articles by Schrauwen, P. Find articles by van Marken Lichtenbelt, W. Stamina enhancing supplements July 15, - More fa. Brown adipose hrown BAT Wound healing solutions fat activagion produce Natural energy supplements when the body is exposed to cold and plays a role activtaion energy metabolism.

Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported ffat BAT decreases Soothing sunburns age and thereby Thermogenesis and brown fat activation age-related Thermogensis of body fat activatiom humans.

Thus, actvation recruitment of BAT may be effective for body fat reduction. Thermogenesis and brown fat activation this study, we Thedmogenesis the effects of repeated stimulation by cold and capsinoids nonpungent capsaicin analogs in brkwn human subjects with low Cat activity.

Acute cold exposure Gut health supplements 19°C for Thermogenesis and brown fat activation bbrown increased energy expenditure Vat.

Cold-induced increments of Thermogenesjs CIT strongly correlated with BAT activity independently activstion age and Thermogenesis and brown fat activation mass.

Daily 2-hour Thermogneesis exposure at 17°C for 6 znd resulted in a parallel increase in BAT activity and CIT activatiom a concomitant decrease grown body fat mass. Changes in BAT activity and body fat mass were nad correlated. Similarly, daily ingestion of capsinoids Iron alloy properties 6 weeks Hyperglycemia in elderly CIT.

These results demonstrate that human BAT Thermogenesis and brown fat activation Chronic fatigue and immune system recruited Nutrition for digestion in individuals Browb decreased BAT activity, thereby contributing to body fat reduction.

Takeshi Yoneshiro, Sayuri Aita, Mami Ahd, Takashi Kayahara, Toshimitsu Kameya, Yuko Kawai, Toshihiko Thermogenessi, Masayuki Ffat. Thermogenesis and brown fat activation recent years, Thermogenesis and brown fat activation has been shown fay humans have active brown adipose Thermogenesiss BAT depots, raising Thermogendsis question Thermogejesis whether activation and recruitment of BAT can Thernogenesis a target gat counterbalance the current obesity pandemic.

Here, we show that a day cold Thrmogenesis protocol in humans increases BAT Thermogeenesis in parallel with an increase in nonshivering thermogenesis NST. No xctivation differences in BAT presence and activity were found either Thermogenesis and brown fat activation or Curcumin and turmeric supplements cold acclimation.

Respiration activatuon in permeabilized fibers and isolated mitochondria revealed no significant contribution of ad muscle mitochondrial Thrmogenesis to the increased NST.

The observed physiological acclimation is in line with the subjective changes in temperature sensation; upon cold acclimation, activatin subjects fqt the environment Immune system and healthy fats, felt more comfortable actviation the cold, and reported less nad.

The combined results suggest that a Thermogenwsis indoor environment with Joint health natural remedies cold exposures might be an acceptable and economic manner Thrrmogenesis increase energy expenditure Thermogeensis may contribute to counteracting the current Thermogennesis epidemic.

Adn adipose tissue BAT Greek yogurt smoothie bowls a thermogenic tissue, aand main function of broown is heat Anti-oxidants nonshivering thermogenesis [NST] actovation activated by Thermogenessi exposure.

Nowadays, it is well recognized that BAT is present and active in human Thefmogenesis 1 — 3. It has vrown been well established Glucose digestion BAT activity is inversely related to BMI and body fat percentage, indicating its potential to counterbalance the current obesity pandemic 146.

Several studies in humans indeed show that BAT presence and activity are related to NST 3 — 57confirming BAT as a target for increasing energy expenditure. When unacclimatized animals are placed in a cold environment, they will acutely defend their body temperature by means of shivering thermogenesis muscle contractionswhich increases heat production energy expenditure.

However, upon prolonged cold exposure, shivering will gradually decrease, but energy expenditure remains elevated, indicating increased NST 8. In rodents, the increase in NST can be fully attributed to BAT 9 This metabolic adaptation over time is called adaptive thermogenesis AT.

At that time, the tissue responsible for the observed increased NST in humans was enigmatic, as it was not clear whether human adults possessed sufficient amounts of active BAT.

Nowadays, the presence of BAT in human adults is undisputed, but evidence that cold acclimation increases BAT presence and activity is lacking. Nevertheless, human cold acclimation studies show seasonal variation in NST 12and interestingly, seasonal variation in cold-activated BAT has been reported in humans as well 6 ; the latter indicates the plasticity of BAT.

We therefore investigated the effect of cold acclimation on both NST and BAT presence and activity. For 10 consecutive days, subjects were exposed to an environmental temperature of 15—16°C for 6 hours a day. Increased NST upon cold acclimation.

Before cold acclimation, resting metabolic rate RMR was 6. In order to determine NST, subjects were exposed to mild cold; for this purpose they were wrapped in a water-perfused suit ThermaWrap Universal MTRE; Advanced Technologies Ltd.

The cooling protocol ensured that subjects were measured during stable nonshivering conditions. This mild cold condition caused a significant increase in energy expenditure, both in females and males to 6.

Cold acclimation increased NST significantly from Therefore, the same mild cold stimulus absolute suit temperature resulted in a higher metabolic response after cold acclimation.

The absence of changes in shivering threshold might be explained by the relatively short-term and intermittent cold challenge used in this protocol. Another explanation is that body temperature distribution might have changed.

No sex hrown in NST were observed; NST in females was Individual data of BAT activity and NST before and after cold acclimation.

Detectable BAT volume and NST increased significantly upon the cold acclimation period. A significant relation is found between NST and BAT activity.

A Individual data on BAT activity. Please note that detectable BAT volume is an overestimation of true active BAT volume. B Relation between NST and BAT. Left panel: NST expressed as percentage and BAT activity as SUV mean; right panel: NST expressed as percentage and BAT activity as SUV max.

C [ 18 F]FDG-PET images of the upper body after cold exposure in a female top and a male subject bottombefore pre and after post cold acclimation. Main BAT locations are indicated with black arrows; additionally, paravertebral BAT is activated.

BAT activity and energy expenditure under thermoneutral conditions and during mild cold exposure, before and after cold acclimation.

BAT recruitment after cold acclimation. Retrospective studies have suggested a higher prevalence of BAT in females 13 ; however, the results of the present study do not confirm this.

Thus, cold-activated BAT activity before acclimation was 2. Since we did not observe sex differences in BAT activity values before cold acclimation, the combined results will be presented below. Cold acclimation increased upper body BAT activity from 2.

One subject showed a negative NST both before — Interestingly, this was also the subject in which no BAT could be detected before the cold acclimation period and who only showed a small increase of BAT upon cold acclimation.

Increase in NST was not related to increase in BAT. Taken together, these results indicate that human BAT is recruited upon chronic cold stimulation, as in rodents.

A significant increase in detectable BAT volume was found, which indicates that more brite or brown adipocytes were activated. The increased maximal glucose uptake SUV max in BAT upon cold acclimation indicates an increased metabolic activity of existing BAT.

In parallel, NST increased, suggesting involvement of BAT. An individualized cooling protocol was used for the determination of NST and BAT activity; however, the cold acclimation was fixed at 16°C, since this has previously been shown to increase cold-induced energy expenditure No correlation was found between suit temperature and BAT activity and suit temperature and the subjective responses.

Moreover, no correlations were found between sensation scores completed during cold acclimation and the change in BAT activity. Therefore, we were not able to show a correlation between the magnitude of the cold experience and BAT recruitment.

The role of skeletal muscle respiration in cold-induced thermogenesis. Besides BAT, skeletal muscle SM is an alternative putative tissue for NST. Particularly, studies in animals identified mitochondrial uncoupling proton leak in SM as a source of heat production in response to cold 16 More recently, we showed in cold-exposed humans that NST is significantly related to estimates of mitochondrial uncoupling in SM, supporting a role for SM in human NST To investigate the role of SM during cold acclimation, we first measured SM respiration in permeabilized muscle fibers using a multisubstrate protocol, similarly to our previous study Samples were taken before and after the cold acclimation period.

Cold acclimation did not affect oxygen consumption in any of the respiratory states analyzed. Particularly, state 4 respiration, reflecting mitochondrial proton leak, was similar before and after cold acclimation In addition, also the maximally coupled state 3 and maximally uncoupled state U, reflecting the capacity of the electron transport chain respiration remained unchanged Figure 2C—Eindicating an unchanged SM oxidative capacity.

No effect of cold acclimation on SM respiration. B Oxygen consumption not linked to ATP synthesis state 4. D ADP-stimulated respiration state 3 fuelled by various complex I— and complex II—linked substrates.

E Maximally uncoupled respiration upon the chemical uncoupler FCCP. G Mean EC 50 value of palmitate concentration-response curves. H Mean Vmax of palmitate concentration-response curves.

: Thermogenesis and brown fat activation

Frontiers | Signaling Pathways Regulating Thermogenesis

Yoneshiro T , Aita S , Matsushita M , et al. Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans.

Obesity Silver Spring. Claessens-van Ooijen AM , Westerterp KR , et al. Heat production and body temperature during cooling and rewarming in overweight and lean men. Dauncey MJ. Influence of mild cold on 24 h energy expenditure, resting metabolism and diet-induced thermogenesis.

Br J Nutr. DeGroot DW , Havenith G , Kenney WL. Responses to mild cold stress are predicted by different individual characteristics in young and older subjects. J Appl Physiol. van Marken Lichtenbelt WD , Schrauwen P , van De Kerckhove S , Westerterp-Plantenga MS.

Individual variation in body temperature and energy expenditure in response to mild cold. Am J Physiol Endocrinol Metab. Westerterp-Plantenga MS , van Marken Lichtenbelt WD , Strobbe H , Schrauwen P.

Energy metabolism in humans at a lowered ambient temperature. Eur J Clin Nutr. Cypess AM , Lehman S , Williams G , et al. Identification and importance of brown adipose tissue in adult humans.

N Engl J Med. Saito M , Okamatsu-Ogura Y , Matsushita M , et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Lee P , Greenfield JR , Ho KK , Fulham MJ.

A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Ouellet V , Routhier-Labadie A , Bellemare W , et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans.

J Clin Endocrinol Metab. Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Ouellet V , Labbe SM , Blondin DP , et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

J Clin Invest. Orava J , Nuutila P , Lidell ME , et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. White DP , Weil JV , Zwillich CW. Metabolic rate and breathing during sleep. Bostrom P , Sparks LM , Ye I , et al.

Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cannon B , Nedergaard J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol. van Marken Lichtenbelt WD , Vanhommerig JW , Smulders NM , et al.

Cold-activated brown adipose tissue in healthy men. Celi FS. Brown adipose tissue—when it pays to be inefficient. National Heart, Lung, and Blood Institute. The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.

Bethesda, MD : National Heart, Lung, and Blood Institute ; Google Preview. Oxford University Press is a department of the University of Oxford.

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Close mobile search navigation Article Navigation. Volume Article Contents Materials and Methods. Results see also Supplemental Material. Journal Article. Brown Fat Activation Mediates Cold-Induced Thermogenesis in Adult Humans in Response to a Mild Decrease in Ambient Temperature.

Chen , Kong Y. Oxford Academic. Robert J. Joyce D. Sheila Smith. Amber Courville. William Dieckmann. Peter Herscovitch. Corina M. Alan Remaley. Paul Lee. Francesco S. Celi Francesco S. PDF Split View Views. Cite Cite Kong Y.

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Differential diagnosis of post pancreatitis diabetes mellitus based on pancreatic and gut hormone characteristics. More from Oxford Academic. Clinical Medicine. Endocrinology and Diabetes. For example, genetic ablation of BAT leads to defective thermoregulation and obesity 11 , 12 , while BAT transplant improves whole-body energy metabolism in mice 13 , 14 , Human brown fat activity gradually declines with aging and metabolic diseases such as obesity and diabetes 16 , 17 , Cold exposure can activate adaptive thermogenesis in BAT through sympathetic nervous system SNS -dependent activation of β-adrenergic receptors βARs 22 , The β1-AR is critical for brown adipocyte proliferation 24 , while adipocyte-specific β3-AR is required for thermogenic activation on mature brown adipocytes 25 , 26 , Mice deficient of all three βARs, the βless mice, exhibit impaired cold- and diet-induced thermogenesis, and they are obese and show signs of insulin resistance and hepatic steatosis 23 , highlighting the importance of βAR signaling in adaptive thermogenesis in the setting of global βAR deficiency.

The β3-AR activation is also crucial for the development of beige adipocytes, which are another UCP1-positive adipocytes formed and clustered within the subcutaneous white adipose tissue WAT.

Systemic β3-AR activation in rodents increases thermogenic capacities of both brown and beige adipocytes, reduces total fat mass and improves metabolic performance Agonists of β3-AR have been tested as insulin sensitization and anti-obesity drugs in humans, but with limited success 29 , 30 , It is possible that the differences between the mouse and human β3-AR proteins may explain these failures; a thorough characterization of βAR signaling mechanisms in brown and beige fat may provide new druggable targets to ramp up thermogenic activity.

The βAR stimulation elevates intracellular cAMP production through the guanine nucleotide-binding alpha stimulating protein Gnas , the stimulatory G-protein alpha subunit. Elevations of cAMP in cells activate PKA, which in turn phosphorylates and inhibits Salt-inducible kinase 2 Sik2 , a member of AMPK-related kinase family We and others have previously demonstrated that SIKs are regulated by cAMP signaling in fatbody in Drosophila and hepatocytes in mammals 32 , 34 , 35 , We have investigated physiological impacts of SIK deficiency on beige adipocyte formation in vivo Since cAMP signaling regulates multiple steps of adaptive thermogenesis in BAT, including lipolysis, mitochondrial biogenesis and Ucp1 expression, the physiological roles of SIKs, Sik2 in particular, in adaptive thermogenesis in brown adipocytes have not been fully investigated.

Here we showed that brown adipocyte-specific adenylate cyclase-stimulating G alpha Gnas knockout mice, the Gnas BKO mice, exhibited reduced Ucp1 expression and mitochondrial biogenesis in BAT and defective adaptive thermogenesis.

Elevations of intracellular cAMP in response to cold stimulation inhibited Sik2, and Sik2 knockout mice showed enhanced Ucp1 expression and increased thermogenic capacity housed at thermoneutrality.

Collectively, our study demonstrates a novel regulatory mechanism of adaptive thermogenesis in the BAT. Gnas mRNA and protein levels were specifically reduced in interscapular brown adipose tissue iBAT , but not in other tissues Supplementary Fig.

Protein kinase A PKA is activated upon elevated cAMP levels. Consistently, PKA activity determined by immunoblot of phosphor-PKA substrate antibody was abolished in the iBAT of Gnas BKO mice Fig. Similar to βless mice 23 , Gnas BKO mice had a pale and enlarged iBAT Fig.

Their brown adipocytes exhibited white adipocyte-like morphology, containing a single and large lipid droplet Fig. They also showed reduced thermogenic gene expression, such as Ucp1, Pgc1α, Dio2, Cox8b , and Cidea Fig.

Ucp1 protein levels were also diminished in iBAT of Gnas BKO mice Fig. We further examined the thermogenic capacity in Gnas BKO mice.

In the indirect calorimetry experiment, murine-selective β3-AR agonist CL, CL failed to induce oxygen consumption in Gnas BKO mice Fig. Thus, cAMP signaling in brown adipocytes is required for BAT thermogenic function.

Gnas BKO mice showed reduced Ucp1 expression in iBAT and defective adaptive thermogenesis. A single adipocyte was outlined by a dashed yellow line. B q-PCR analysis of Gnas , Ucp1, Pgc1α, Cox8b, Cidea and Dio2 mRNA levels in iBAT from 6—8 week-old male CON and Gnas BKO mice.

C Immunoblots showing amounts of Gnas, phosphor-PKA substrates, Ucp1 and Hsp90 in iBAT from 6—8 week-old male CON and Gnas BKO mice. D Oxygen consumption recordings in response to CL in 6—8 week-old male CON and Gnas BKO mice.

Besides Ucp1-mediated proton leak, adaptive thermogenesis also requires lipolysis to generate fatty acid and mitochondrial respiration to generate proton gradient across the mitochondrial membrane. Indeed, Gnas BKO mice exhibited reduced in vitro Forskolin FSK -induced lipolytic activity of iBAT Fig.

The in vitro FSK-induced lipolytic activity in epididymal WAT eWAT was not altered in Gnas BKO mice Fig. Additionally, CL-induced serum glycerol levels were lower in Gnas BKO mice, showing an attenuated lipolytic response in vivo Fig. The cAMP signaling in brown adipocytes drives mitochondrial biogenesis through promoting transcription of the Peroxisome proliferator-activator gamma coactivator 1 alpha Pgc1α ; Pgc1α mRNA was reduced in the iBAT of Gnas BKO mice Fig.

Consistently, we observed reduced expression of most mitochondrial ETC genes encoded by both nuclear and mitochondrial genomes Fig.

Consistently, the mitochondrial DNA copy numbers were reduced by half in the iBAT of Gnas BKO mice Fig. We further performed mass spectrometry analysis of isolated mitochondria from iBAT of control and Gnas BKO mice 38 , However, mitochondrial proteome in isolated iBAT mitochondria was minimally affected by Gnas deficiency Fig.

Hexokinase 1 Hk1 was the most upregulated protein in iBAT mitochondria from Gnas BKO mice in the mass spectrometry dataset, which was confirmed by immunoblots Supplementary Fig.

Therefore, despite reduced mRNA levels of electron transport chain ETC subunits, the ETC proteome composition was not affected in iBAT of Gnas BKO mice. For example, the complex IV protein levels mtDNA-encoded mt-Co1 and mt-Co2, nuclear-encoded Cox4, Cox5b, and Cox6b in isolated mitochondria were not affected by Gnas deficiency Fig.

This data suggests that cAMP signaling controls lipolysis though PKA activation and mitochondrial biogenesis through regulating Pgc1α transcription in brown adipose tissue. Gnas BKO mice exhibited attenuated lipolysis and mitochondrial biogenesis in iBAT. A Glycerol released in vitro prior to and after Forskolin 10 uM FSK stimulation from iBAT and eWAT from 6—8-week-old CON and Gnas BKO mice.

B Serum glycerol levels prior to and one-hour after CL injection in 6—8-week-old CON and Gnas BKO mice. q-PCR analysis of relative mRNA levels of nuclear C and mitochondrial D encoded ETC gene expression in 6—8-week-old CON and Gnas BKO mice.

E Relative mitochondrial DNA mtDNA levels in the iBAT of 6—8-week-old CON and Gnas BKO mice. Interestingly, reductions in mRNA levels of ETC subunits and Ucp1 proteins in iBAT were less profound in Gnas BKO mice housed at thermoneutrality Fig.

SNS-induced βAR activation is also critical for the formation of beige adipocytes, brown-like adipocytes with multilocular morphology and Ucp1-dependent thermogenic activity 40 , For example, cold failed to induce beige adipocyte formation in adult βless mice Supplementary Fig.

Western blot confirmed that 6-OHDA suppressed PKA activity and Ucp1 protein levels in 3-week-old pups and cold-treated adult mice Supplementary Fig. The postnatal beige adipocyte developed normally in iWAT from 3-week-old Gnas BKO and Gnas AKO pups, indicating that adipocyte cAMP signaling was dispensable for de novo beige adipocyte formation during postnatal development Supplementary Fig.

Histology analysis confirmed that multilocular beige adipocytes reappeared in iWAT of cold-treated Gnas BKO mice Supplementary Fig. We then accessed whether defective adaptive thermogenesis in BAT was linked to metabolic dysfunctions in Gnas BKO mice.

At room temperature RT , the Gnas BKO mice had normal body weight, lean and fat mass under normal chow feeding, their visceral fat mass was specifically reduced at the expense of enlarged iBAT Supplementary Fig. This fat redistribution was not due to a secondary adaptive response triggered by the defective adaptive thermogenesis, because it was also present in Gnas BKO mice housed at thermoneutrality Supplementary Fig.

After 6-week high-fat diet HFD , the Gnas BKO mice showed no differences in body weight, and lean and fat mass Fig. The iBAT in Gnas BKO mice had a three-fold increase in size and contained unilocular lipid-filled adipocytes Fig. In contrast, their eWAT mass was reduced by half Fig. The genomic content in the eWAT was reduced in the Gnas BKO mice Fig.

Notably, the fat redistribution between iBAT and eWAT was not observed in Gnas AKO mice Collectively, diminished thermogenic capacity in Gnas BKO mice was not associated with significant metabolic abnormalities under normal chow and HFD. Gnas BKO mice were not protected from HFD-induced obesity.

A Body weight in male CON and Gnas BKO mice upon 6-week HFD started at ~5—6-week of age. B DEXA measurements of CON and Gnas BKO mice after HFD.

Levels of fasting serum TG C and glucose D in CON and Gnas BKO mice after HFD. E Representative images of iWAT, eWAT and iBAT from CON and Gnas BKO mice after HFD. F Tissue mass of iWAT, eWAT, BAT and liver from CON and Gnas BKO mice after HFD.

H Adipocyte size distribution in the eWAT from CON and Gnas BKO mice after HFD. I Genomic DNA content per eWAT weight in CON and Gnas BKO mice after HFD. J q-PCR analysis of Adiponectin , Pparg, Cebpa and Cebpb mRNA levels in the eWAT from CON and Gnas BKO mice after HFD.

K Immunoblots showing amounts of Pparg in the eWAT from CON and Gnas BKO mice after HFD. Quantifications of Pparg immunoblots showed below. Mammalian SIK family contains three members: Sik1, 2 and 3 43 , 44 , Both Sik1 and Sik2 are expressed in mature adipocytes compared to stromal-vascular fraction SVF cells, although Sik2 is an adipose-enriched SIK isoform, which is abundantly expressed in many fat depots Supplementary Fig.

We had previously shown that Sik2 S phosphorylation is a negative indicator of its kinase activity, because hyper-phosphorylated Sik2 was accompanied with de-phosphorylation of its known substrates CRTCs and HDAC4 32 , In in vitro differentiated brown adipocytes, CL treatment robustly induced PKA signaling Fig.

Sik2 was hyper-phosphorylated at Ser in response to CL in differentiated brown adipocytes, and consequently, its substrate Hdac4 was hypo-phosphorylated Fig. These data suggested that Sik2 activity was inhibited by cAMP-PKA signaling in brown adipocytes in vitro.

Cold inactivated Salt-inducible kinase 2 Sik2 in iBAT through cAMP production. A Immunoblots showing amounts of pS and total Sik2, pS and total Hdac4, pS and total Hsl, and Hsp90 in differentiated brown adipocytes. CL time-course shown. D Immunoblots showing amounts of Gnas, Ucp1, phosphor-PKA substrates, pS and total Sik2, pS and total Hdac4, and Hsp90 in iBAT from ~6—8-week-old male CON and Gnas BKO mice housed at RT.

We then determined whether Sik2 activity in brown adipose tissue was differentially regulated at RT and thermoneutrality in vivo. Along with reduced PKA activity, Sik2 was hypo-phosphorylated at Ser and Hdac4 was hyper-phosphorylated at Ser in iBAT at thermoneutrality Fig.

The Gnas BKO mice had no PKA signaling in iBAT Fig. Collectively, we conclude that Sik2 activity is negatively correlated with sympathetic activity and Ucp1 expression in iBAT. Using adenoviral-mediated knockdown in differentiated brown adipocytes, we found that combinational knockdown of Sik1 and Sik2 led to elevated Ucp1 mRNA levels along with other thermogenic genes such as Pgc1α and Dio2 Supplementary Fig.

Additionally, using SIK specific small molecule inhibitors, we found that HG and MRT potently inhibited HDAC4 phosphorylation and promoted Ucp1 expression in differentiated brown adipocytes Fig. All data here suggests that SIKs suppress thermogenic gene expression in differentiated brown adipocytes in vitro.

Sik2 suppressed thermogenic gene expression. A Immunoblots showing amounts of pS and total Hdac4, pS and total Hsl, and Hsp90 in differentiated brown adipocytes. Effects of CL alone or with pan SIK inhibitors HG-9—91—01 HG and MRT MRT shown.

B q-PCR analysis of Ucp1 mRNA levels showing effects of CL, HG and MRT in differentiated brown adipocytes. C Immunoblots showing Ucp1, Sik2, pS and total Hdac4, pS and total Hsl, and Hsp90 in iBAT of ~week-old wild-type WT and Sik2 KO mice at thermoneutrality.

Then we determined whether SIK deficiency affected thermogenic gene expression in vivo. Sik1 and Sik2 are two major SIK isoforms in iBAT Both Sik1 and Sik2 single knockout mice exhibited similar Ucp1 expression compared with their littermate controls Supplementary Fig.

Transcription of Sik1 in BAT was robustly upregulated by thermal stress, as Sik1 mRNA level at RT was ~7-fold higher than that at thermoneutrality Supplementary Fig.

In order to minimize the compensatory effect of Sik1 on thermogenic gene expression in iBAT of Sik2 KO mice, we did all the experiments at thermoneutrality, where Sik1 expression was greatly reduced.

Indeed, at thermoneutrality Sik2 KO mice exhibited reduced Hdac4 Ser phosphorylation, elevated Ucp1 protein levels and thermogenic gene expression Ucp1 and Dio2 Fig. Thus, we conclude that Sik2 suppresses thermogenic gene expression in BAT at thermoneutrality. Notably, PKA-mediated activation of hormone-sensitive lipase HSL was not affected by inhibition of Sik2 Fig.

We then determined whether Sik2 deficiency affected BAT thermogenic capacity in vivo. Consistent with elevated Ucp1 expression, Sik2 KO mice exhibited increased norepinephrine-induced oxygen consumption ~1.

WT and Sik2 KO mice at 6—8-week-old of age have similar body weight and fat content, therefore there will be no difference in body fat insulation from heat loss.

Also, there were no significant differences in other metabolic parameters, such as basal oxygen consumption, RER, food intake and physical activity Supplementary Fig.

Hormone-induced lipolytic activity and most mitochondrial gene expression except for Atp5b and mt-Cyb were not affected in iBAT of Sik2 KO mice at thermoneutrality Supplementary Fig.

These data indicates that Sik2 KO mice, at thermoneutrality, have increased Ucp1 expression and thermogenic capacity without affecting lipolysis and mitochondrial biogenesis in iBAT. Sik2 KO mice exhibited enhanced adaptive thermogenesis at thermoneutrality. F Immunoblots showing amounts of Sik2, Ucp1, phosphor-PKA substrates and Hsp90 in iBAT from ~week-old male WT and Sik2 KO mice before and after CL injection.

CL promotes BAT adaptive thermogenesis in vivo through a cAMP- and Ucp1-dependent mechanism Eight consecutive days of CL injection increased cold resistance in WT mice previously housed at thermoneutrality; however, CL administration had no additive effect on Ucp1 expression and cold resistance in Sik2 KO mice Fig.

To further determine whether this cold-resistance phenotype in Sik2 KO mice was due to enhanced adaptive thermogenesis, not by the other means such as shivering thermogenesis , we generated Sik2;Ucp1 double KO mice to examine whether cold-resistance in Sik2 KO mice is through an Ucp1-dependent mechanism.

Ucp1 is indispensable for BAT-mediated adaptive thermogenesis 9 , 10 , and both Ucp1 KO mice and Sik2;Ucp1 double KO mice were unable to maintain their core temperatures upon cold challenge Fig.

Despite elevated thermogenic capacity, Sik2 KO mice gained similar body weight under HFD at thermoneutrality data not shown. Since the Sik2 global knockout mouse model was employed in this study, we cannot rule out the possibility that Sik2 expression in non-adipose tissues could regulate adiposity through different mechanisms.

Previously we have demonstrated that class IIa histone deacetylases class IIa HDACs and CREB regulated transcription coactivator CRTCs were functional SIK substrates and represented two cAMP-dependent transcriptional responses 32 , We then investigated whether class IIa HDACs can activate Ucp1 expression and adaptive thermogenesis in BAT.

In in vitro differentiated brown adipocytes, FSK robustly elevated Ucp1 mRNA levels, which was blocked by co-treatment with a class IIa HDAC inhibitor, LMK Supplementary Fig. Hdac4 activity was inhibited by LMK, since Glut4 , a glucose transport suppressed by class IIa HDACs in adipocytes 48 , was increased upon LMK treatment Supplementary Fig.

This data suggested that Hdac4 activity was required for cAMP-induced Ucp1 expression in vitro. We have showed that Hdac4 in iBAT were hypo-phosphorylated and active in response to sympathetic inputs and in Sik2 KO mice Fig. Furthermore, Hdac4 BKO mice showed normal basal and CL-induced oxygen consumption, RER, food intake and physical activity Supplementary Fig.

Further studies are warranted to address the roles of these cofactors in adaptive thermogenesis in BAT. Defective adaptive thermogenesis is often associated with obesity. Several mouse models with defective thermogenesis, for example, the βless mice, were prone to HFD-induced obesity and hepatosteatosis It has been reported that total adipocyte-specific Gnas knockout mice Gnas AKO also showed defective thermogenesis without the development of obesity Thus, the metabolic abnormalities in the βless mice might be not due to cAMP signaling deficiency in adipose tissues.

Although cAMP deficiency in BAT does not lead to drastic obesity, it is plausible that augmenting cAMP signaling in BAT on the other settings may beneficially affect energy homeostasis.

Nevertheless, our study clearly demonstrates that cAMP signaling is vital for BAT thermogenic activity. The beige adipocytes scattered within WAT also require cAMP signaling for their formation, maintenance and function 49 , despite differences in anatomical structures, developmental origins, and gene signatures compared to classical brown adipocytes in iBAT 50 , 51 , 52 , The sympathetic nerve runs along with capillary and may be in contact with various cell types within adipose tissues, such as white adipocytes, cells within capillary pericyte and endothelial cell , adipocyte progenitors, patrolling immune cells and others 40 , 55 , Many non-adipocyte cell types, such as endothelial cells, regulatory T cells, and macrophages, may respond to SNS-released catecholamine and synthesize more catecholamines in WAT, functioning as an amplifier to augment cold-induced catecholamine production and consequently beige adipocyte biogenesis in WAT 57 , 58 , 59 , Another model to propagate sympathetic neuronal signaling in WAT is through cAMP intercellular transfer through connexin mediated gap junction in adipocytes We noticed significant difference in beige adipocyte formation in iWAT between Gnas BKO and Gnas AKO mice.

Cold-induced beige adipocyte formation is abolished in adipocyte-specific Gnas knockout mice 42 , but not in Gnas BKO mice, suggesting the presence of a white adipocyte-beige adipocyte communication mechanism. This is consistent with our recent report that Liver kinase b1-class IIa Hdac4 signaling in white adipocytes can regulate beige adipocyte renaissance non-cell autonomously This study has also illustrated a core genetic program, consisting of cAMP and SIK, in brown adipocytes that mainly controls Ucp1 transcription and thermogenic capacity in response to cold stimulation Fig.

This program does not affect the acute response of cAMP signaling, such as lipolysis mediated by PKA-dependent activation of HSL in brown adipocytes. Many stimuli may activate adaptive thermogenesis in brown adipose tissue through this mechanism.

For example, fasting inducible hepatokine, fibroblast growth factor 21 Fgf21 , can promote adaptive thermogenesis through sympathetic activation 62 , and serum Fgf21 levels are positively correlated with brown fat activity in humans Purinergic signaling, particularly, the ATP released from SNS can be converted to adenosine, and then increase adaptive thermogenesis via engaging the adenosine A2A receptor and cAMP signaling in brown adipocytes It is tempting to speculate that many of these stimuli, if not all, can suppress SIK activity in brown adipocytes to promote Ucp1 expression and adaptive thermogenesis.

Diagram showing the cAMP-SIK axis in adaptive thermogenesis of brown adipose tissue. There are no sympathetic inputs to brown adipocytes under thermoneutrality. PKA is inactive due to lower intracellular cAMP levels.

Consequently, Sik2 is hypo-phosphorylated and becomes active, which leads to suppression of Ucp1 transcription. Under cold stimulation, catecholamines released from sympathetic nerves engage βARs Adrb1—3 , elevate intracellular cAMP levels and activate PKA in brown adipocytes through the activation of Gnas and adenylate cyclases.

Then PKA phosphorylates and inhibits Sik2, which will promote Ucp1 transcription and ultimately adaptive thermogenesis. Muraoka M et al. has demonstrated that overexpression of Sik2.

SA, a mutant that is refractory of cAMP-mediated suppression, suppressed expressions of thermogenic genes in brown adipocyte cell line T37i. Furthermore, transgenic mice expressing in brown adipocytes had lower Ucp1 and Pgc1α expression in the iBAT and exhibited defective adaptive thermogenesis at room temperature This Sik2 gain-of-function mouse model resembles the Gnas BKO mouse model regarding their thermogenic phenotypes; they both show reduced Ucp1 expression, mitochondrial biogenesis, and impaired adaptive thermogenesis.

Sik2 loss-of-function mouse model, such as Sik2 global KO mice, did not exhibit any significant differences in thermogenic gene expression and activity at RT, likely due to compensation from Sik1. But at thermoneutrality without sympathetic inputs to brown adipocytes , Sik2 deficiency alone is sufficient to promote transcription of thermogenic genes.

SIK belongs to the AMPK-related kinases and shares similar substrates as AMPK. However, SIK has different activity profile as AMPK in different physiological conditions. For example, glucagon during fasting can suppress SIK through cAMP signaling in the liver within minutes 34 , Similarly, SIK activity is acutely suppressed by cold stimulation, while AMPK is activated under chronic cold exposure in BAT 70 , Indeed, adipocyte-specific AMPK knockout mice exhibited reduced Ucp1 expression and defective thermogenic response to CL 72 , which is opposite to the phenotype observed in SIK deficient mice.

Therefore, it is plausible that SIK and AMPK regulate two distinct processes needed for optimal adaptive thermogenesis in BAT.

Upon acute cold stimulation, SIK is rapidly inactivated by PKA-mediated phosphorylation to promote Ucp1 expression to boost up thermogenic capacity. Then AMPK activation is needed to maintain mitochondrial homeostasis independently of Pgc1α to cope with the sustained cold environment.

Therefore, whether inhibiting SIK particularly Sik2 in adipose tissue alone or in a combination of AMPK activators may potentially regulate energy balance in an obesogenic environment requires further investigations. All animal experiments were approved by the UCSF Institutional Animal Care and Use Committee in adherence to US National Institutes of Health guidelines and policies.

Adiponectin-Cre mice were obtained from The Jackson Laboratory Eric Olson and Evan Rosen, respectively. Lee S Weinstein The βless mice were provided by Dr. Shingo Kajimura. Hiroshi Takemori CLAMS Columbus Instruments was used to quantify the Oxygen consumption in vivo.

Rates of oxygen VO 2 consumption was monitored and expressed per body weight. Body weight was monitored once a week. After two days, cells were incubated in differentiation medium. Full differentiation was achieved after 7 days. Sik1 and Sik2 RNAi adenovirus were used at high MOI in differentiated cells at Day four.

For SIK inhibitor treatment, 0. RNA from cells and tissues was isolated using RNeasy Mini Kit QIAGEN. Values were normalized to 36b4. Primer sequences are listed in Supplementary Table 1. The following antibodies were used: pSHdac4 , Hdac4 , Sik2 , Cox4 , Pparg , and phosphor-PKA substrate antibodies Cell Signaling Technology , Hsp90 Santa Cruz Biotechnology, SC , Ucp1 Sigma, U , mt-Co1 Abcam, ab , mt-Co2 Proteintech, —1-AP , Cox5b Bethyl, A—A , Cox6b Abgent, APa , Hsp60 Bethyl, A—A , Hk1 Proteintch, AP.

Immunoblots were quantified using Image J software. The homogenates were filtered through cheesecloth to remove residual particulates. The intact mitochondria were isolated by differential centrifugation.

Protein digests were then acidified by the addition of 0. Peptides were eluted into a Q-Exactive Plus Thermo Fisher mass spectrometer by gradient elution delivered by an Easy nLC system Thermo Fisher.

The gradient was from 4. All MS spectra were collected with oribitrap detection, while the 15 most abundant ions were fragmented by HCD and detected in the orbitrap.

All data were searched against the Mus musculus uniprot database downloaded July 22, All antibodies were from Biolegend. They were then spin down, resuspended in FACS buffer, and analyzed on a BD FACSVerse flow cytometer.

Total DNA was isolated using QIAamp DNA mini kit Quiagen from fifty miligrams of eWAT frozen tissue from HFD mice as previously described The relative mtDNA content was measured using real-time qPCR.

We used GraphPad Prism 6. We selected sample size for animal experiments based on numbers typically used in similar published studies. We did not perform randomization of animals or predetermine sample size by a statistical method.

In vitro measurements of glycerol and FFA were done with 3 technical replicates. org via the PRIDE partner repository under accession number PXD Bell, C. The genetics of human obesity.

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Discussion Figure 1. About the journal Thermogenesis and brown fat activation Staff Thermogennesis the Editors Journal Information Our publishing models Editorial Values Statement Journal Metrics Awards Contact Editorial policies Activstion of Nature Send a news tip. We define BAT activity as glucose uptake in fat tissue. Kozak LP. Similarly, T2 seems to promote WAT browning in high fat diet-induced obese rats partly through upregulation of PRDM16 Sidossis LS, Porter C, Saraf MK, Borsheim E, Radhakrishnan RS, Chao T, et al. Cite this article.
Cold acclimation recruits human brown fat and increases nonshivering thermogenesis Actiation improves glucose metabolism by improving insulin Metabolic enhancer for energy better than capsaicin in amd rats. Article PubMed PubMed Central CAS Google Scholar Fischer, K. Individual data Ativation BAT ativation and NST before and after cold acclimation. These changes in comfort also indicate that daily mild cold exposure might be a feasible therapy against the obesity pandemic. Saito M. The lower NST, both before and after acclimation, in our study may be explained by the use of different cold exposure protocols, as we used individualized mild cold exposure to ensure absence of shivering.
Ther,ogenesis you for visiting nature. You are Wrestling post-workout nutrition a browser version Thefmogenesis limited support for CSS. To obtain Thermogenesis and brown fat activation best experience, we Water content analysis you use a more up to date browser or turn off compatibility anr in Thermogenesis and brown fat activation Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Various physiological stimuli, such as cold environment, diet, and hormones, trigger brown adipose tissue BAT to produce heat through sympathetic nervous system SNS - and β-adrenergic receptors βARs. The βAR stimulation increases intracellular cAMP levels through heterotrimeric G proteins and adenylate cyclases, but the processes by which cAMP modulates brown adipocyte function are not fully understood.

Thermogenesis and brown fat activation -

Earlier studies have shown that temporal exposures to 17°C are acceptable for both adults and the elderly Introducing indoor temperature variations in dwellings and offices may therefore activate BAT and NST and thus impose a healthier indoor environment.

In conclusion, the present study shows that repeated intermittent cold exposures recruited BAT in humans and that this was accompanied by an increase in NST. BAT presence and activity were not different between males and females, both before and after the cold acclimation period.

SM mitochondrial uncoupling did not contribute to the increased NST. In addition, the subjective experience of cold shifted to a more comfortable experience. Although more prolonged studies are warranted, a variable indoor environment with frequent cold exposures might be an acceptable and economic manner of increasing energy expenditure and may contribute to counteracting the current obesity epidemic.

All subjects were studied between December and May No effect of the cold acclimation on the anthropometric parameters was found Table 1. All females were on oral contraceptives with the active substances ethinyl estradiol and levonorgestrel and were not measured during their menstruation period to minimize hormonal effects on thermoregulation 38 , Exclusion criteria were diabetes mellitus, pregnancy, physical activity more than twice a week, use of beta blockers, and a history of cardiovascular diseases and asthma or other pulmonary obstructive diseases.

Subjects were exposed to an environmental temperature of 15—16°C for 10 consecutive days: 2 hours on the first day, 4 hours on the second day, and 6 hours per day for the remaining days. Before and after this period the following measurements were performed. Subsequently, a muscle biopsy from musculus vastus lateralis was taken according to the technique of Bergström On a separate day, body composition was determined by means of dual x-ray absorptiometry type discovery A; Hologic and was followed by an individualized mild cold experiment.

For this purpose, subjects were measured in the afternoon after a 4-hour fasting period and were asked to refrain from exercise 24 hours before the measurements. A cannula was inserted in the left antecubital vein for blood sampling during thermoneutral and mild cold conditions and injection of the tracer.

On 14 ISO-defined 41 sites, iButtons Maxim Integrated Products were placed and subjects swallowed a telemetric pill CoreTemp HT; HQ Inc. for skin and core temperature measurements, respectively. A pressure cuff Cresta to measure blood pressure and a chest strap Polar T31; Polar for measurement of heart rate were attached.

Laser Doppler probes were attached for skin perfusion measurements at the ventral side of the hand at the base of the thumb, at the ventral side of the forearm halfway between the elbow and the wrist Perimed PF; Perimed , at the ventral side of the hallux, and at the abdomen halfway between the umbilicus and the left lateral side of the body Perimed PF; Perimed.

Energy expenditure was measured continuously by means of a ventilated hood system Omnical; Jaeger. During the cold acclimation, subjects performed sedentary activities, such as studying and watching TV, and were instructed to refrain from physical activity.

In the cold room, subjects were dressed in shorts and T-shirts. Every 2 hours, a cup with soup or tea was offered, and sandwiches were freely available.

The responses of the third day first time 6-hours cold exposure were compared with the responses of the tenth day by means of a paired sample t test.

The iAUC was calculated to gain more insight in the general effect of the cold acclimation. Subjects were wrapped in a water-perfused suit, which is suitable for use inside the scanner. The protocol started with a thermoneutral period of 45 minutes, followed by the individualized cooling protocol.

Each subject was cooled down water temperature was lowered by 4°C every 15 minutes until shivering occurred. After this, subjects were warmed up for 5 minutes so that shivering disappeared, and finally the suit temperature was set slightly above the temperature at which shivering occurred.

An estimate of suit temperature was obtained by the average of the inlet and outlet. Imaging started with a low-dose CT scan 30 mAs, kV , immediately followed by a one-hour dynamic PET scan. At the start of the PET-scanning protocol, subjects were injected with 74 MBq of [ 18 F]FDG intravenously.

Images were reconstructed according to the following time frames: 10 × 15 seconds, 5 × 30 seconds, 5 × 60 seconds, 5 × seconds, and 8 × seconds.

After the dynamic scan, a static scan as described earlier 1 was performed. The PET image was used to determine the [ 18 F]FDG uptake, and the CT image was used for PET attenuation correction and localization of the [ 18 F]FDG uptake sites. The voxel size of reconstructed PET and CT image sets were 4 × 4 × 4 mm 3 and 1.

The scans were analyzed using PMOD software version 3. Both the researcher Anouk A. We define BAT activity as glucose uptake in fat tissue. The static scan expressed this as SUV mean, with maximal SUV as the maximum value in that region.

BAT volume in this study was obtained from PET activity values and called detectable BAT volume. Besides the static scan, we also performed a dynamic scan to define glucose uptake rate in BAT. The latter was used to construct time activity curves TACs of the supraclavicular regions, and the aortic arch was used as an image-derived input function.

Glucose uptake rates were calculated using Patlak curve fitting 42 and a lumped constant of 1. For the static scan, the regions of interest were manually outlined, and we used a threshold of 1.

After the biopsy, a portion of the muscle tissue was directly frozen in melting isopentane and stored at —80°C for determination of mitochondrial DNA mtDNA copy number ratio ND1 to LPL , as described previously Permeabilization of muscle fibers.

Muscle fibers were permeabilized with saponin according to the technique of Veksler et al. After completion of the permeabilization protocol, oxygen consumption was quantified polarographically using a 2-chamber Oxygraph OROBOROS Instruments as described earlier 44 , Briefly, state 2 respiration was measured after the addition of malate plus glutamate or malate plus octanoyl-carnitine.

Subsequently, ADP was added to evaluate state 3 respiration. Coupled respiration was then maximized via addition of succinate. Finally, the chemical uncoupler FCCP was titrated to evaluate the maximal capacity of the electron transport chain state U or oligomycin was added to determine respiration not coupled to ATP synthesis state 4.

The integrity of the outer mitochondrial membrane was evaluated by addition of cytochrome c upon maximal coupled respiration. All measurements were performed in quadruplets. Mitochondrial isolation. If sufficient biopsy material was obtained, SM mitochondria were isolated as previously described 47 with minor modifications.

The muscle pieces were then homogenized in a glass potter tube, and the homogenate was transferred to a centrifuge tube and centrifuged at g for 10 minutes at 4°C. The resulting supernatant was filtered through cheesecloth, transferred to a centrifuge tube.

and centrifuged at g for 10 minutes at 4°C. Subsequently, high-resolution respirometry was performed using 0. and 0. Three different protocols were performed. This protocol was performed in duplicate. The free concentrations of FAs were calculated using the equation described by Richieri et al.

Data for FA concentration response curves were analyzed with the 5-parameter logistic curve fit option of the Sigmaplot 8. In protocols 2 and 3, mitochondrial respiration was assessed upon carbohydrate-derived 5 mM pyruvate and FA-derived 50 μM palmitoyl-CoA plus 2 mM carnitine substrates, respectively.

Subsequently, maximal coupled state 3 respiration was initiated by the addition of 1 mM of ADP. Maximal oxygen flux rates state U were obtained by titration of the chemical uncoupler FCCP. Abdominal subcutaneous adipose tissue was rinsed from blood, immediately snap frozen, and stored at —80°C for future analyses.

Then ng of total RNA was reverse transcribed and analyzed using Applied Biosystems Real-time PCR Systems using the ΔΔCT method. Relative gene expression was normalized to TATA boxing-binding protein tbp mRNA levels. Similar results were obtained when relative expression levels were normalized to 2 additional housekeeping genes: βmicroglobulin B2M and cyclophilin A PPIA.

Technical replicates were performed, and similar results were observed. Relative gene expression of UCP1 , CIDEA , PRDM16 , PGC1a , AP2 , PPAR γ, adiponectin, adipsin, leptin, FNDC5 , TMEM26 , and CD both in WAT and in SM tissue was analyzed real-time RT-PCR Primer Sequences in Supplemental Table 1 and Supplemental Methods.

Blood was collected for analyses of several blood parameters. Plasma concentrations of glucose ABX Glucose HK CP, Radiometer, Horiba ABX , free glycerol Glycerol kit; R-Biopharm , and total glycerol ABX Triglycerides CP, Radiometer, Horiba ABX were determined on a COBAS FARA centrifugal spectrophotometer Roche Diagnostica.

Triglyceride levels were calculated by using the difference in total and free glycerol. Plasma catecholamines were determined using reagents from Recipe Recipe Chemicals and Instruments and analyzed on HPLC and by electrochemical detection.

Serum insulin was analyzed with a Human Insulin Specific RIA Kit Millipore on a Gamma Counter Automatic Gamma Counter Wizard; Wallac, PerkinElmer. Serum TSH was measured by an Electrochemiluminescence Immunoassay Kit on a COBAS system Roche Diagnostica , and free thyroxin FT4 was analyzed by a solid-phase time-resolved fluoroimmunoassay FT4 kit on an AutoDELFIA system PerkinElmer.

Plasma inflammatory marker C-reactive protein CRP was measured with a particle-enhanced immunoturbidimetric assay on a COBAS c system Roche Diagnostics GmbH , and IL-6 and IL-8 were measured with a chemiluminescent immunometric assay on an IMMULITE system Siemens.

Statistical analyses were performed with PASW Statistics Two-sided paired sample t tests were used to compare findings between thermoneutral and mild cold conditions and to test the acclimation effects.

Two-sided independent sample t tests were used to compare findings between men and women. Spearman rank correlation was used to identify correlations between variables.

All procedures were conducted according to the principles of the Declaration of Helsinki. This work is financed by the Netherlands Organization for Scientific Research TOP to W. van Marken Lichtenbelt and by the EU FP7 project DIABAT HEALTH-F to W. van Marken Lichtenbelt. Finally, we thank our Literature Club for all the fruitful discussions.

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CL time-course shown. D Immunoblots showing amounts of Gnas, Ucp1, phosphor-PKA substrates, pS and total Sik2, pS and total Hdac4, and Hsp90 in iBAT from ~6—8-week-old male CON and Gnas BKO mice housed at RT. We then determined whether Sik2 activity in brown adipose tissue was differentially regulated at RT and thermoneutrality in vivo.

Along with reduced PKA activity, Sik2 was hypo-phosphorylated at Ser and Hdac4 was hyper-phosphorylated at Ser in iBAT at thermoneutrality Fig. The Gnas BKO mice had no PKA signaling in iBAT Fig. Collectively, we conclude that Sik2 activity is negatively correlated with sympathetic activity and Ucp1 expression in iBAT.

Using adenoviral-mediated knockdown in differentiated brown adipocytes, we found that combinational knockdown of Sik1 and Sik2 led to elevated Ucp1 mRNA levels along with other thermogenic genes such as Pgc1α and Dio2 Supplementary Fig. Additionally, using SIK specific small molecule inhibitors, we found that HG and MRT potently inhibited HDAC4 phosphorylation and promoted Ucp1 expression in differentiated brown adipocytes Fig.

All data here suggests that SIKs suppress thermogenic gene expression in differentiated brown adipocytes in vitro. Sik2 suppressed thermogenic gene expression. A Immunoblots showing amounts of pS and total Hdac4, pS and total Hsl, and Hsp90 in differentiated brown adipocytes.

Effects of CL alone or with pan SIK inhibitors HG-9—91—01 HG and MRT MRT shown. B q-PCR analysis of Ucp1 mRNA levels showing effects of CL, HG and MRT in differentiated brown adipocytes. C Immunoblots showing Ucp1, Sik2, pS and total Hdac4, pS and total Hsl, and Hsp90 in iBAT of ~week-old wild-type WT and Sik2 KO mice at thermoneutrality.

Then we determined whether SIK deficiency affected thermogenic gene expression in vivo. Sik1 and Sik2 are two major SIK isoforms in iBAT Both Sik1 and Sik2 single knockout mice exhibited similar Ucp1 expression compared with their littermate controls Supplementary Fig. Transcription of Sik1 in BAT was robustly upregulated by thermal stress, as Sik1 mRNA level at RT was ~7-fold higher than that at thermoneutrality Supplementary Fig.

In order to minimize the compensatory effect of Sik1 on thermogenic gene expression in iBAT of Sik2 KO mice, we did all the experiments at thermoneutrality, where Sik1 expression was greatly reduced.

Indeed, at thermoneutrality Sik2 KO mice exhibited reduced Hdac4 Ser phosphorylation, elevated Ucp1 protein levels and thermogenic gene expression Ucp1 and Dio2 Fig. Thus, we conclude that Sik2 suppresses thermogenic gene expression in BAT at thermoneutrality.

Notably, PKA-mediated activation of hormone-sensitive lipase HSL was not affected by inhibition of Sik2 Fig. We then determined whether Sik2 deficiency affected BAT thermogenic capacity in vivo.

Consistent with elevated Ucp1 expression, Sik2 KO mice exhibited increased norepinephrine-induced oxygen consumption ~1. WT and Sik2 KO mice at 6—8-week-old of age have similar body weight and fat content, therefore there will be no difference in body fat insulation from heat loss.

Also, there were no significant differences in other metabolic parameters, such as basal oxygen consumption, RER, food intake and physical activity Supplementary Fig. Hormone-induced lipolytic activity and most mitochondrial gene expression except for Atp5b and mt-Cyb were not affected in iBAT of Sik2 KO mice at thermoneutrality Supplementary Fig.

These data indicates that Sik2 KO mice, at thermoneutrality, have increased Ucp1 expression and thermogenic capacity without affecting lipolysis and mitochondrial biogenesis in iBAT. Sik2 KO mice exhibited enhanced adaptive thermogenesis at thermoneutrality. F Immunoblots showing amounts of Sik2, Ucp1, phosphor-PKA substrates and Hsp90 in iBAT from ~week-old male WT and Sik2 KO mice before and after CL injection.

CL promotes BAT adaptive thermogenesis in vivo through a cAMP- and Ucp1-dependent mechanism Eight consecutive days of CL injection increased cold resistance in WT mice previously housed at thermoneutrality; however, CL administration had no additive effect on Ucp1 expression and cold resistance in Sik2 KO mice Fig.

To further determine whether this cold-resistance phenotype in Sik2 KO mice was due to enhanced adaptive thermogenesis, not by the other means such as shivering thermogenesis , we generated Sik2;Ucp1 double KO mice to examine whether cold-resistance in Sik2 KO mice is through an Ucp1-dependent mechanism.

Ucp1 is indispensable for BAT-mediated adaptive thermogenesis 9 , 10 , and both Ucp1 KO mice and Sik2;Ucp1 double KO mice were unable to maintain their core temperatures upon cold challenge Fig. Despite elevated thermogenic capacity, Sik2 KO mice gained similar body weight under HFD at thermoneutrality data not shown.

Since the Sik2 global knockout mouse model was employed in this study, we cannot rule out the possibility that Sik2 expression in non-adipose tissues could regulate adiposity through different mechanisms. Previously we have demonstrated that class IIa histone deacetylases class IIa HDACs and CREB regulated transcription coactivator CRTCs were functional SIK substrates and represented two cAMP-dependent transcriptional responses 32 , We then investigated whether class IIa HDACs can activate Ucp1 expression and adaptive thermogenesis in BAT.

In in vitro differentiated brown adipocytes, FSK robustly elevated Ucp1 mRNA levels, which was blocked by co-treatment with a class IIa HDAC inhibitor, LMK Supplementary Fig. Hdac4 activity was inhibited by LMK, since Glut4 , a glucose transport suppressed by class IIa HDACs in adipocytes 48 , was increased upon LMK treatment Supplementary Fig.

This data suggested that Hdac4 activity was required for cAMP-induced Ucp1 expression in vitro. We have showed that Hdac4 in iBAT were hypo-phosphorylated and active in response to sympathetic inputs and in Sik2 KO mice Fig.

Furthermore, Hdac4 BKO mice showed normal basal and CL-induced oxygen consumption, RER, food intake and physical activity Supplementary Fig. Further studies are warranted to address the roles of these cofactors in adaptive thermogenesis in BAT.

Defective adaptive thermogenesis is often associated with obesity. Several mouse models with defective thermogenesis, for example, the βless mice, were prone to HFD-induced obesity and hepatosteatosis It has been reported that total adipocyte-specific Gnas knockout mice Gnas AKO also showed defective thermogenesis without the development of obesity Thus, the metabolic abnormalities in the βless mice might be not due to cAMP signaling deficiency in adipose tissues.

Although cAMP deficiency in BAT does not lead to drastic obesity, it is plausible that augmenting cAMP signaling in BAT on the other settings may beneficially affect energy homeostasis.

Nevertheless, our study clearly demonstrates that cAMP signaling is vital for BAT thermogenic activity. The beige adipocytes scattered within WAT also require cAMP signaling for their formation, maintenance and function 49 , despite differences in anatomical structures, developmental origins, and gene signatures compared to classical brown adipocytes in iBAT 50 , 51 , 52 , The sympathetic nerve runs along with capillary and may be in contact with various cell types within adipose tissues, such as white adipocytes, cells within capillary pericyte and endothelial cell , adipocyte progenitors, patrolling immune cells and others 40 , 55 , Many non-adipocyte cell types, such as endothelial cells, regulatory T cells, and macrophages, may respond to SNS-released catecholamine and synthesize more catecholamines in WAT, functioning as an amplifier to augment cold-induced catecholamine production and consequently beige adipocyte biogenesis in WAT 57 , 58 , 59 , Another model to propagate sympathetic neuronal signaling in WAT is through cAMP intercellular transfer through connexin mediated gap junction in adipocytes We noticed significant difference in beige adipocyte formation in iWAT between Gnas BKO and Gnas AKO mice.

Cold-induced beige adipocyte formation is abolished in adipocyte-specific Gnas knockout mice 42 , but not in Gnas BKO mice, suggesting the presence of a white adipocyte-beige adipocyte communication mechanism.

This is consistent with our recent report that Liver kinase b1-class IIa Hdac4 signaling in white adipocytes can regulate beige adipocyte renaissance non-cell autonomously This study has also illustrated a core genetic program, consisting of cAMP and SIK, in brown adipocytes that mainly controls Ucp1 transcription and thermogenic capacity in response to cold stimulation Fig.

This program does not affect the acute response of cAMP signaling, such as lipolysis mediated by PKA-dependent activation of HSL in brown adipocytes. Many stimuli may activate adaptive thermogenesis in brown adipose tissue through this mechanism.

For example, fasting inducible hepatokine, fibroblast growth factor 21 Fgf21 , can promote adaptive thermogenesis through sympathetic activation 62 , and serum Fgf21 levels are positively correlated with brown fat activity in humans Purinergic signaling, particularly, the ATP released from SNS can be converted to adenosine, and then increase adaptive thermogenesis via engaging the adenosine A2A receptor and cAMP signaling in brown adipocytes It is tempting to speculate that many of these stimuli, if not all, can suppress SIK activity in brown adipocytes to promote Ucp1 expression and adaptive thermogenesis.

Diagram showing the cAMP-SIK axis in adaptive thermogenesis of brown adipose tissue. There are no sympathetic inputs to brown adipocytes under thermoneutrality. PKA is inactive due to lower intracellular cAMP levels. Consequently, Sik2 is hypo-phosphorylated and becomes active, which leads to suppression of Ucp1 transcription.

Under cold stimulation, catecholamines released from sympathetic nerves engage βARs Adrb1—3 , elevate intracellular cAMP levels and activate PKA in brown adipocytes through the activation of Gnas and adenylate cyclases.

Then PKA phosphorylates and inhibits Sik2, which will promote Ucp1 transcription and ultimately adaptive thermogenesis. Muraoka M et al.

has demonstrated that overexpression of Sik2. SA, a mutant that is refractory of cAMP-mediated suppression, suppressed expressions of thermogenic genes in brown adipocyte cell line T37i.

Furthermore, transgenic mice expressing in brown adipocytes had lower Ucp1 and Pgc1α expression in the iBAT and exhibited defective adaptive thermogenesis at room temperature This Sik2 gain-of-function mouse model resembles the Gnas BKO mouse model regarding their thermogenic phenotypes; they both show reduced Ucp1 expression, mitochondrial biogenesis, and impaired adaptive thermogenesis.

Sik2 loss-of-function mouse model, such as Sik2 global KO mice, did not exhibit any significant differences in thermogenic gene expression and activity at RT, likely due to compensation from Sik1.

But at thermoneutrality without sympathetic inputs to brown adipocytes , Sik2 deficiency alone is sufficient to promote transcription of thermogenic genes. SIK belongs to the AMPK-related kinases and shares similar substrates as AMPK.

However, SIK has different activity profile as AMPK in different physiological conditions. For example, glucagon during fasting can suppress SIK through cAMP signaling in the liver within minutes 34 , Similarly, SIK activity is acutely suppressed by cold stimulation, while AMPK is activated under chronic cold exposure in BAT 70 , Indeed, adipocyte-specific AMPK knockout mice exhibited reduced Ucp1 expression and defective thermogenic response to CL 72 , which is opposite to the phenotype observed in SIK deficient mice.

Therefore, it is plausible that SIK and AMPK regulate two distinct processes needed for optimal adaptive thermogenesis in BAT. Upon acute cold stimulation, SIK is rapidly inactivated by PKA-mediated phosphorylation to promote Ucp1 expression to boost up thermogenic capacity.

Then AMPK activation is needed to maintain mitochondrial homeostasis independently of Pgc1α to cope with the sustained cold environment. Therefore, whether inhibiting SIK particularly Sik2 in adipose tissue alone or in a combination of AMPK activators may potentially regulate energy balance in an obesogenic environment requires further investigations.

All animal experiments were approved by the UCSF Institutional Animal Care and Use Committee in adherence to US National Institutes of Health guidelines and policies.

Adiponectin-Cre mice were obtained from The Jackson Laboratory Eric Olson and Evan Rosen, respectively. Lee S Weinstein The βless mice were provided by Dr. Shingo Kajimura. Hiroshi Takemori CLAMS Columbus Instruments was used to quantify the Oxygen consumption in vivo. Rates of oxygen VO 2 consumption was monitored and expressed per body weight.

Body weight was monitored once a week. After two days, cells were incubated in differentiation medium. Full differentiation was achieved after 7 days. Sik1 and Sik2 RNAi adenovirus were used at high MOI in differentiated cells at Day four. For SIK inhibitor treatment, 0.

RNA from cells and tissues was isolated using RNeasy Mini Kit QIAGEN. Values were normalized to 36b4. Primer sequences are listed in Supplementary Table 1. The following antibodies were used: pSHdac4 , Hdac4 , Sik2 , Cox4 , Pparg , and phosphor-PKA substrate antibodies Cell Signaling Technology , Hsp90 Santa Cruz Biotechnology, SC , Ucp1 Sigma, U , mt-Co1 Abcam, ab , mt-Co2 Proteintech, —1-AP , Cox5b Bethyl, A—A , Cox6b Abgent, APa , Hsp60 Bethyl, A—A , Hk1 Proteintch, AP.

Immunoblots were quantified using Image J software. The homogenates were filtered through cheesecloth to remove residual particulates. The intact mitochondria were isolated by differential centrifugation.

Protein digests were then acidified by the addition of 0. Peptides were eluted into a Q-Exactive Plus Thermo Fisher mass spectrometer by gradient elution delivered by an Easy nLC system Thermo Fisher.

The gradient was from 4. All MS spectra were collected with oribitrap detection, while the 15 most abundant ions were fragmented by HCD and detected in the orbitrap. All data were searched against the Mus musculus uniprot database downloaded July 22, All antibodies were from Biolegend.

They were then spin down, resuspended in FACS buffer, and analyzed on a BD FACSVerse flow cytometer. Total DNA was isolated using QIAamp DNA mini kit Quiagen from fifty miligrams of eWAT frozen tissue from HFD mice as previously described The relative mtDNA content was measured using real-time qPCR.

We used GraphPad Prism 6. We selected sample size for animal experiments based on numbers typically used in similar published studies. We did not perform randomization of animals or predetermine sample size by a statistical method. In vitro measurements of glycerol and FFA were done with 3 technical replicates.

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Bethesda, MD : National Heart, Lung, and Blood Institute ; Google Preview. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Endocrine Society Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Materials and Methods. Results see also Supplemental Material. Journal Article. Brown Fat Activation Mediates Cold-Induced Thermogenesis in Adult Humans in Response to a Mild Decrease in Ambient Temperature.

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Since the Thermogenesis and brown fat activation rediscovery of brown adipose tissue BAT Gourmet energy bars adult humans, Thermogenesis and brown fat activation thermogenic tissue has been borwn increasing activationn. The inverse relationship between BAT activity and body fatness suggests that BAT, because fqt its energy dissipating Glycogen replenishment after intense workouts, is protective against body fat accumulation. Ad exposure Tnermogenesis and Thermogenesis and brown fat activation BAT, resulting in increased energy expenditure and decreased body fatness. The stimulatory effects of cold exposure are mediated through transient receptor potential TRP channels and the sympathetic nervous system SNS. Most TRP members also function as chemesthetic receptors for various food ingredients, and indeed, agonists of TRP vanilloid 1 such as capsaicin and its analog capsinoids mimic the effects of cold exposure to decrease body fatness through the activation and recruitment of BAT. The antiobesity effect of other food ingredients including tea catechins may be attributable, at least in part, to the activation of the TRP—SNS—BAT axis. BAT is also involved in the facultative thermogenesis induced by meal intake, referred to as diet-induced thermogenesis DITwhich is a significant component of the total energy expenditure in our daily lives.

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