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Thermogenesis and thermogenic agents

Thermogenesis and thermogenic agents

Yao, J. However, emerging evidence suggests that ahd fat uses UCP1-independent thermogenic pathways, which substantially contribute to systemic energy homeostasis. Recruited vs.

Thermogenesis and thermogenic agents -

Pyruvate dehydrogenase complex plays a central role in brown adipocyte energy expenditure and fuel utilization during short-term beta-adrenergic activation. Sci Rep ; 8 : Irshad Z , Dimitri F , Christian M , Zammit VA.

Diacylglycerol acyltransferase 2 links glucose utilization to fatty acid oxidation in the brown adipocytes. J Lipid Res ; 58 : 15 — Wu J , Bostrom P , Sparks LM , Ye L , Choi JH , Giang AH , Khandekar M , Virtanen KA , Nuutila P , Schaart G , Huang K , Tu H , van Marken Lichtenbelt WD , Hoeks J , Enerback S , Schrauwen P , Spiegelman BM.

Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Sharp LZ , Shinoda K , Ohno H , Scheel DW , Tomoda E , Ruiz L , Hu H , Wang L , Pavlova Z , Gilsanz V , Kajimura S.

PLoS One ; 7 : e Jespersen NZ , Larsen TJ , Peijs L , Daugaard S , Homøe P , Loft A , de Jong J , Mathur N , Cannon B , Nedergaard J , Pedersen BK , Møller K , Scheele C. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans.

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Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med ; 19 : — Nedergaard J , Cannon B. How brown is brown fat? It depends where you look. Finlin BS , Memetimin H , Confides AL , Kasza I , Zhu B , Vekaria HJ , Harfmann B , Jones KA , Johnson ZR , Westgate PM , Alexander CM , Sullivan PG , Dupont-Versteegden EE , Kern PA.

Human adipose beiging in response to cold and mirabegron. JCI Insight ; 3 : e Perwitz N , Wenzel J , Wagner I , Büning J , Drenckhan M , Zarse K , Ristow M , Lilienthal W , Lehnert H , Klein J. Cannabinoid type 1 receptor blockade induces transdifferentiation towards a brown fat phenotype in white adipocytes.

Diabetes Obes Metab ; 12 : — Vitali A , Murano I , Zingaretti MC , Frontini A , Ricquier D , Cinti S. J Lipid Res ; 53 : — Lee YH , Petkova AP , Konkar AA , Granneman JG. Cellular origins of cold-induced brown adipocytes in adult mice. Himms-Hagen J , Melnyk A , Zingaretti MC , Ceresi E , Barbatelli G , Cinti S.

Multilocular fat cells in WAT of CLtreated rats derive directly from white adipocytes. Am J Physiol Cell Physiol ; : C — C Harms MJ , Li Q , Lee S , Zhang C , Kull B , Hallen S , Thorell A , Alexandersson I , Hagberg CE , Peng XR , Mardinoglu A , Spalding KL , Boucher J.

Mature human white adipocytes cultured under membranes maintain identity, function, and can transdifferentiate into brown-like adipocytes. Cell Rep ; 27 : — Lee YH , Petkova AP , Mottillo EP , Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding.

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Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci U S A ; : — Petrovic N , Walden TB , Shabalina IG , Timmons JA , Cannon B , Nedergaard J.

Chronic peroxisome proliferator-activated receptor gamma PPARgamma activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes.

J Biol Chem ; : — Vegiopoulos A , Müller-Decker K , Strzoda D , Schmitt I , Chichelnitskiy E , Ostertag A , Berriel Diaz M , Rozman J , de Angelis M H , Nüsing RM , Meyer CW , Wahli W , Klingenspor M , Herzig S.

Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science ; : — Shao M , Wang QA , Song A , Vishvanath L , Busbuso NC , Scherer PE , Gupta RK.

Cellular origins of beige fat cells revisited. Diabetes ; 68 : — Bartelt A , Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol ; 10 : 24 — Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis.

Cell Metab ; 18 : — Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis. Bartelt A , John C , Schaltenberg N , Berbée JFP , Worthmann A , Cherradi ML , Schlein C , Piepenburg J , Boon MR , Rinninger F , Heine M , Toedter K , Niemeier A , Nilsson SK , Fischer M , Wijers SL , van Marken Lichtenbelt W , Scheja L , Rensen PCN , Heeren J.

Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport. Nat Commun ; 8 : Hoeke G , Wang Y , van Dam AD , Mol IM , Gart E , Klop HG , van den Berg SM , Pieterman EH , Princen HMG , Groen AK , Rensen PCN , Berbée JFP , Boon MR.

Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis.

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Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL receptor versus hepatic remnant receptor in vivo. J Lipid Res ; 38 : — Ramasamy I. Recent advances in physiological lipoprotein metabolism.

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Effects of pharmacological thermogenic adipocyte activation on metabolism and atherosclerotic plaque regression. Nutrients ; 11 : van Vlijmen BJ , van den Maagdenberg AM , Gijbels MJ , van der Boom H , HogenEsch H , Frants RR , Hofker MH , Havekes LM.

Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice. J Clin Invest ; 93 : — de Haan W , de Vries-van der Weij J , van der Hoorn JW , Gautier T , van der Hoogt CC , Westerterp M , Romijn JA , Jukema JW , Havekes LM , Princen HM , Rensen PC.

Torcetrapib does not reduce atherosclerosis beyond atorvastatin and induces more proinflammatory lesions than atorvastatin. Circulation ; : — Schwartz GG , Steg PG , Szarek M , Bhatt DL , Bittner VA , Diaz R , Edelberg JM , Goodman SG , Hanotin C , Harrington RA , Jukema JW , Lecorps G , Mahaffey KW , Moryusef A , Pordy R , Quintero K , Roe MT , Sasiela WJ , Tamby JF , Tricoci P , White HD , Zeiher AM.

Alirocumab and cardiovascular outcomes after acute coronary syndrome. Sabatine MS , Giugliano RP , Keech AC , Honarpour N , Wiviott SD , Murphy SA , Kuder JF , Wang H , Liu T , Wasserman SM , Sever PS , Pedersen TR.

Evolocumab and clinical outcomes in patients with cardiovascular disease. Tavori H , Giunzioni I , Fazio S. PCSK9 Inhibition to reduce cardiovascular disease risk: recent findings from the biology of PCSK9.

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Effect of bile acid sequestrants on the risk of cardiovascular events: a Mendelian randomization analysis. Circ Cardiovasc Genet ; 8 : — Raiko J , Orava J , Savisto N , Virtanen KA. High brown fat activity correlates with cardiovascular risk factor levels cross-sectionally and subclinical atherosclerosis at 5-year follow-up.

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Arterial wall uptake of fluorodeoxyglucose on PET imaging in stable cancer disease patients indicates higher risk for cardiovascular events. J Nucl Cardiol ; 15 : — Heaton JM. The distribution of brown adipose tissue in the human.

J Anat ; : 35 — Jespersen NZ , Andersen MW , Jensen VH , Stærkær TW , Severinsen MCK , Peijs L , Soares R , Forss I , Andersen ES , Hahn CH , Homøe P , Mandrup S , Pedersen BK , Nielsen S , Scheele C.

Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity. bioRxiv doi: Vijgen GH , Bouvy ND , Teule GJ , Brans B , Schrauwen P , van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One ; 6 : e O'Mara AE , Johnson JW , Linderman JD , Brychta RJ , McGehee S , Fletcher LA , Fink YA , Kapuria D , Cassimatis TM , Kelsey N , Cero C , Sater ZA , Piccinini F , Baskin AS , Leitner BP , Cai H , Millo CM , Dieckmann W , Walter M , Javitt NB , Rotman Y , Walter PJ , Ader M , Bergman RN , Herscovitch P , Chen KY , Cypess AM.

Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. Nahon KJ , Janssen LGM , Sardjoe Mishre ASD , Bilsen MP , van der Eijk JA , Botani K , Overduin LA , Ruiz JR , Burakiewicz J , Dzyubachyk O , Webb AG , Kan HE , Berbee JFP , van Klinken JB , van Dijk KW , van Weeghel M , Vaz FM , Coskun T , Jazet IM , Kooijman S , Martinez-Tellez B , Boon MR , Rensen PCN.

The effect of mirabegron on energy expenditure and brown adipose tissue in healthy lean south Asian and europid men. Diabetes Obes Metab ; 22 : — Chondronikola M , Volpi E , Børsheim E , Porter C , Annamalai P , Enerbäck S , Lidell ME , Saraf MK , Labbe SM , Hurren NM , Yfanti C , Chao T , Andersen CR , Cesani F , Hawkins H , Sidossis LS.

Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes ; 63 : — Yoneshiro T , Aita S , Matsushita M , Kayahara T , Kameya T , Kawai Y , Iwanaga T , Saito M. Recruited brown adipose tissue as an antiobesity agent in humans. Hanssen MJ , van der Lans AA , Brans B , Hoeks J , Jardon KM , Schaart G , Mottaghy FM , Schrauwen P , van Marken Lichtenbelt WD.

Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes ; 65 : — Lee P , Smith S , Linderman J , Courville AB , Brychta RJ , Dieckmann W , Werner CD , Chen KY , Celi FS. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Cypess AM , Weiner LS , Roberts-Toler C , Franquet Elía E , Kessler SH , Kahn PA , English J , Chatman K , Trauger SA , Doria A , Kolodny GM.

Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab ; 21 : 33 — Baskin AS , Linderman JD , Brychta RJ , McGehee S , Anflick-Chames E , Cero C , Johnson JW , O'Mara AE , Fletcher LA , Leitner BP , Duckworth CJ , Huang S , Cai H , Garraffo HM , Millo CM , Dieckmann W , Tolstikov V , Chen EY , Gao F , Narain NR , Kiebish MA , Walter PJ , Herscovitch P , Chen KY , Cypess AM.

Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by a β3-adrenergic receptor agonist. Diabetes ; 67 : — Finlin BS , Memetimin H , Zhu B , Confides AL , Vekaria HJ , El Khouli RH , Johnson ZR , Westgate PM , Chen J , Morris AJ , Sullivan PG , Dupont-Versteegden EE , Kern PA.

The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. Larsen TM , Toubro S , van Baak MA , Gottesdiener KM , Larson P , Saris WH , Astrup A.

Effect of a d treatment with L, a novel beta 3 -adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr ; 76 : — Redman LM , de Jonge L , Fang X , Gamlin B , Recker D , Greenway FL , Smith SR , Ravussin E.

Lack of an effect of a novel beta3-adrenoceptor agonist, TAK, on energy metabolism in obese individuals: a double-blind, placebo-controlled randomized study. J Clin Endocrinol Metab ; 92 : — Wibmer AG , Becher T , Eljalby M , Crane A , Andrieu PC , Jiang CS , Vaughan R , Schöder H , Cohen P.

Brown adipose tissue is associated with healthier body fat distribution and metabolic benefits independent of regional adiposity. Cell Rep Med ; 2 : Iwen KA , Backhaus J , Cassens M , Waltl M , Hedesan OC , Merkel M , Heeren J , Sina C , Rademacher L , Windjäger A , Haug AR , Kiefer FW , Lehnert H , Schmid SM.

Cold-induced brown adipose tissue activity alters plasma fatty acids and improves glucose metabolism in men. J Clin Endocrinol Metab ; : — Hanssen MJ , Hoeks J , Brans B , van der Lans AA , Schaart G , van den Driessche JJ , Jörgensen JA , Boekschoten MV , Hesselink MK , Havekes B , Kersten S , Mottaghy FM , van Marken Lichtenbelt WD , Schrauwen P.

Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med ; 21 : — Sponton CH , Hosono T , Taura J , Jedrychowski MP , Yoneshiro T , Wang Q , Takahashi M , Matsui Y , Ikeda K , Oguri Y , Tajima K , Shinoda K , Pradhan RN , Chen Y , Brown Z , Roberts LS , Ward CC , Taoka H , Yokoyama Y , Watanabe M , Karasawa H , Nomura DK , Kajimura S.

The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT-liver communication. EMBO Rep ; 21 : e Whitehead A , Krause FN , Moran A , MacCannell ADV , Scragg JL , McNally BD , Boateng E , Murfitt SA , Virtue S , Wright J , Garnham J , Davies GR , Dodgson J , Schneider JE , Murray AJ , Church C , Vidal-Puig A , Witte KK , Griffin JL , Roberts LD.

Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis. Nat Commun ; 12 : The Trp64Arg polymorphism in β3 adrenergic receptor ADRB3 gene is associated with adipokines and plasma lipids: a systematic review, meta-analysis, and meta-regression.

Lipids Health Dis ; 19 : Liggett SB. beta 2 -adrenergic receptor pharmacogenetics. Am J Respir Crit Care Med ; : S — S Brodde OE , Büscher R , Tellkamp R , Radke J , Dhein S , Insel PA. Blunted cardiac responses to receptor activation in subjects with ThrIle beta 2 -adrenoceptors.

Piscione F , Iaccarino G , Galasso G , Cipolletta E , Rao MA , Brevetti G , Piccolo R , Trimarco B , Chiariello M. Effects of Ile polymorphism of beta2-adrenergic receptor gene on coronary artery disease.

J Am Coll Cardiol ; 52 : — Lee P , Day RO , Greenfield JR , Ho KK. Formoterol, a highly β2-selective agonist, increases energy expenditure and fat utilisation in men. Int J Obes Lond ; 37 : — Emanuelli B , Vienberg SG , Smyth G , Cheng C , Stanford KI , Arumugam M , Michael MD , Adams AC , Kharitonenkov A , Kahn CR.

Interplay between FGF21 and insulin action in the liver regulates metabolism. Schlein C , Talukdar S , Heine M , Fischer AW , Krott LM , Nilsson SK , Brenner MB , Heeren J , Scheja L. FGF21 Lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues.

Cell Metab ; 23 : — Liu C , Schönke M , Zhou E , Li Z , Kooijman S , Boon MR , Larsson M , Wallenius K , Dekker N , Barlind L , Peng XR , Wang Y , Rensen PCN.

Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis. Hanssen MJ , Broeders E , Samms RJ , Vosselman MJ , van der Lans AA , Cheng CC , Adams AC , van Marken Lichtenbelt WD , Schrauwen P.

Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci Rep ; 5 : Lee P , Linderman JD , Smith S , Brychta RJ , Wang J , Idelson C , Perron RM , Werner CD , Phan GQ , Kammula US , Kebebew E , Pacak K , Chen KY , Celi FS.

Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab ; 19 : — Lee P , Werner CD , Kebebew E , Celi FS. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes Lond ; 38 : — Gaich G , Chien JY , Fu H , Glass LC , Deeg MA , Holland WL , Kharitonenkov A , Bumol T , Schilske HK , Moller DE.

The effects of LY, an FGF21 analog, in obese human subjects with type 2 diabetes. Talukdar S , Zhou Y , Li D , Rossulek M , Dong J , Somayaji V , Weng Y , Clark R , Lanba A , Owen BM , Brenner MB , Trimmer JK , Gropp KE , Chabot JR , Erion DM , Rolph TP , Goodwin B , Calle RA. A long-acting FGF21 molecule, PF, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects.

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GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Kooijman S , Wang Y , Parlevliet ET , Boon MR , Edelschaap D , Snaterse G , Pijl H , Romijn JA , Rensen PC. Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice.

Diabetologia ; 58 : — Janssen LGM , Nahon KJ , Bracké KFM , van den Broek D , Smit R , Sardjoe Mishre ASD , Koorneef LL , Martinez-Tellez B , Burakiewicz J , Kan HE , van Velden FHP , Pereira Arias-Bouda LM , de Geus-Oei LF , Berbée JFP , Jazet IM , Boon MR , Rensen PCN.

Twelve weeks of exenatide treatment increases [ 18 F]fluorodeoxyglucose uptake by brown adipose tissue without affecting oxidative resting energy expenditure in nondiabetic males. Metab Clin Exp ; : Marso SP , Daniels GH , Brown-Frandsen K , Kristensen P , Mann JF , Nauck MA , Nissen SE , Pocock S , Poulter NR , Ravn LS , Steinberg WM , Stockner M , Zinman B , Bergenstal RM , Buse JB.

Liraglutide and cardiovascular outcomes in type 2 diabetes. Rakipovski G , Rolin B , Nøhr J , Klewe I , Frederiksen KS , Augustin R , Hecksher-Sørensen J , Ingvorsen C , Polex-Wolf J , Knudsen LB.

JACC Basic Transl Sci ; 3 : — Sanada J , Obata A , Obata Y , Fushimi Y , Shimoda M , Kohara K , Nakanishi S , Mune T , Kaku K , Kaneto H. Dulaglutide exerts beneficial anti atherosclerotic effects in ApoE knockout mice with diabetes: the earlier, the better. Sci Rep ; 11 : Wang Y , Parlevliet ET , Geerling JJ , van der Tuin SJ , Zhang H , Bieghs V , Jawad AH , Shiri-Sverdlov R , Bot I , de Jager SC , Havekes LM , Romijn JA , van Dijk K W , Rensen PC.

Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. Br J Pharmacol ; : — Frias JP , Nauck MA , Van J , Kutner ME , Cui X , Benson C , Urva S , Gimeno RE , Milicevic Z , Robins D , Haupt A.

Efficacy and safety of LY, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial.

Lancet ; : — Getty-Kaushik L , Song DH , Boylan MO , Corkey BE , Wolfe MM. Glucose-dependent insulinotropic polypeptide modulates adipocyte lipolysis and reesterification. Obesity Silver Spring ; 14 : — 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. Advertisement intended for healthcare professionals. Navbar Search Filter Cardiovascular Research This issue ESC Publications Cardiovascular Medicine Books Journals Oxford Academic Mobile Enter search term Search.

ESC Publications. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. BAT morphology and physiology.

Beige adipocytes and browning of WAT. Activation of thermogenic adipose tissue counteracts dyslipidaemia and atherosclerosis in the presence of an apolipoprotein E-low-density lipoprotein receptor uptake pathway for TRL remnants.

Stimulation of thermogenesis in adipose tissue augments the beneficial effects of cholesterol-lowering therapies, and vice versa. Human BAT activity inversely relates to CVD incidence. Human BAT activation by cold exposure attenuates risk factors of CVD.

Therapeutic interventions to recruit BAT and promote BAT activity. Concluding remarks and future directions. Data availability. Journal Article. Role of thermogenic adipose tissue in lipid metabolism and atherosclerotic cardiovascular disease: lessons from studies in mice and humans.

Zhixiong Ying , Zhixiong Ying. Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center.

Oxford Academic. Naomi Tramper. Enchen Zhou. Mariëtte R Boon. Patrick C N Rensen. Corresponding author. Sander Kooijman.

Conflict of interest: None declared. Revision received:. Corrected and typeset:. PDF Split View Views. Select Format Select format. ris Mendeley, Papers, Zotero.

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Abstract Brown adipocytes within brown adipose tissue BAT and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Graphical abstract. Open in new tab Download slide. Atherosclerosis , Adipose tissue , Cardiovascular disease , Dyslipidaemia , Non-shivering thermogenesis.

Figure 1. Table 1 Overview of studies investigating the effect of stimulation of thermogenic activity in adipose tissue on plasma lipids in relation to atherosclerosis development in mice. Mouse model. Food intake. Total cholesterol.

Lesion area. LDL-cholesterol instead of non-HDL-cholesterol. KD, knock down. Open in new tab. Figure 2. Figure 3. Google Scholar Crossref. Molecular mechanism of thermogenic induction by small molecules. Activation of cell surface receptors, such as Trpv1, β3-AR, Ptch1 and A2aR, in adipocytes and TrkB in muscles involves cellular signaling cascades PKA, PKG, Sirt1, AMPK and p38 MAPK , transcriptional regulators Prdm family, Pgc-1α, Ppar family and Zfp and cytokines IL-4 and IL to induce Ucp1 expression.

This process also stimulates brown adipocytes followed by Ucp1-mediated heat production. Natural thermogenic small molecules, such as berberine, butein, capsaicin and fucoxanthin, activate thermogenic transcriptional factors through their cell surface receptors or by modulating cellular signaling cascades in adipocytes.

Synthetic thermogenic compounds Ppar agonists, Jak inhibitors, Notch inhibitors, salsalate, β-AR agonists, BAY 41— and DNP can also increase thermogenesis.

Thermogenic small molecules, including serotonin, lactate, BAIBA, nitrate, and adenosine, are endogenously produced upon certain stimuli to increase thermogenic responses. BAIBA and lactate secreted from myocytes upon exercise can act upon white adipocytes and stimulate thermogenic conversion.

A2aR, adenosine A2a receptor; AMPK, AMP-activated protein kinase; β-AR, β-adrenergic receptor; BAIBA, β-aminoisobutyric acid. Ucp1 is a multipass transmembrane protein that is highly expressed in the mitochondria of thermogenic adipocytes, brown adipocytes and beige adipocytes. Ucp1 modulates the proton gradient between the mitochondrial matrix and the intermembrane space and generates heat by uncoupling the respiratory chain with a low rate of ATP production.

Normally, Ucp1 is activated in response to cold exposure. Cold exposure stimulates the secretion of noradrenaline from the sympathetic nervous system, leading to the activation of adrenergic receptors and the stimulation of the thermogenic response in adipocytes.

Most studies related to the thermogenic action of adipocytes have focused on the expression and activity of Ucp1 due to limited knowledge regarding thermogenic enzymes.

Nonetheless, questions have been steadily raised for the presence of Ucp1-independent thermogenic processes. Until recently, the underlying mechanism of Ucp1-independent thermogenic processes has been unclear.

N -Acyl amino acids processed from Pm20d1 can directly bind to the mitochondria and function as endogenous uncouplers, leading to increased mitochondrial respiration to replenish the ATP pool. Mice injected with Pm20d1-containing adenovirus have been found to be protected from diet-induced obesity via an increase in energy expenditure.

PR domain-containing protein 16 Prdm16 was first identified as a powerful transcriptional regulator of brown adipogenesis via modulation of the muscle-to-brown fat switch.

Loss of Prdm4 can increase white adipocyte differentiation while suppressing the expression of thermogenic genes in beige and brown adipocytes. Mice lacking Prdm4 have shown increased weight gain and insulin resistance on a high-fat diet.

Peroxisome proliferator-activated receptor gamma coactivator-1α Pgc-1α was identified as a binding partner of Pparγ in brown adipocytes. β3-Adrenergic receptor agonist or cold exposure can activate MAPK and cAMP signaling to modulate the activity and expression of Pgc-1α.

The ectopic expression of Pgc-1α in white adipocytes induces a brown adipocyte-selective gene program and increases cellular respiration. Interaction of Pgc-1α with Prdm16 and mediator of RNA polymerase II transcription subunit 1 Med1 can increase the expression of Ucp1.

Forkhead box protein c2 Foxc2 is a well-known transcription factor that regulates adipocyte differentiation and metabolism. Foxc2-activated thermogenic adipocytes are mediated by an elevated level of β-adrenergic receptor-PKA signaling, leading to higher Ucp1 expression.

Cold-inducible zinc finger protein Zfp was identified by its interaction with the proximal region of the Ucp1 promoter. Knockout of Zfp has caused embryonic lethality, with a significant reduction in BAT mass. Conversely, adipocyte-specific expression of Zfp can activate thermogenic adipocytes in WAT depots and prevent diet-induced obesity by increasing energy expenditure.

Although intrinsic transcription factors regulating thermogenic adipocytes have been widely studied, extrinsic factors are relatively less elucidated.

One important hormone that induces beige fat from WAT is irisin. Subsequent studies have shown that induction of thermogenic adipocytes by muscle Pgc-1α is mediated by muscle-secreted irisin. Injection of irisin also called fibronectin type III domain-containing protein 5 -expressing adenovirus can induce beige fat formation with increased thermogenic gene program expression, improve glucose metabolism, and increase energy expenditure.

However, its physiological roles in humans remain to be determined. Fibroblast growth factor 21 Fgf21 has been studied as a critical metabolic regulator in multiple organs, including adipose tissues, the liver and the pancreas. Therapeutic doses of Fgf21 can lower glucose levels shortly after being administered in both mice and humans.

The impaired expression of a thermogenic gene program is also associated with a reduced level of Pgc-1α protein in adipocytes.

Type II cytokines, including IL-4 and IL, play beneficial roles in adipose tissue remodeling. Cold exposure activates eosinophils to secrete IL-4 and IL, resulting in alternative activation of macrophages in adipose tissues. These activated macrophages in turn produce catecholamines, resulting in the induction of WAT browning and of the thermogenic capacity of BAT.

Berberine is a natural quaternary ammonium salt found in medicinal herbal plants including barberries Berberis spp. Butein, a naturally occurring chalcone, is isolated from the medicinal Chinese lacquer tree Toxicodendron vernicifluum.

Although the in vivo efficacy of butein in obese or diabetic mice has not yet been demonstrated, butein has been utilized to identify Prdm4 as a key driver of the brown and beige fat gene program.

Prdm4 knockdown and overexpression studies have further revealed that Prdm4 can stimulate Ucp1 expression and increase energy expenditure. Capsaicin is one of the bio-active compounds found in chili peppers. Capsaicin has been shown to be able to activate transient receptor potential cation channel subfamily V member 1 TrpV1 , resulting in anti-obese effects in mice.

This resistance can be explained by increased expression of Ucp1 in muscles accompanied by increased energy expenditure without appetite suppression. Regardless, it is known that 7,8-DHF treatment increases Ucp1 expression and AMPK activity via TrkB tropomyosin-related kinase receptor B in skeletal muscles.

The anti-obese effect of 7,8-DHF is blunted in TrkB-knockout mice, further indicating that TrkB plays a crucial role in 7,8-DHF-mediated anti-obese effects.

Fucoxanthin is a highly enriched carotenoid found in edible seaweeds. These improvements in metabolic parameters are also related to the induction of Ucp1 protein levels in white adipose tissue.

Pparγ, a nuclear receptor, belongs to the class of transcription factors with a characteristic ligand binding domain. Pparγ is regarded as the master regulator of adipogenesis. However, its underlying mechanism remains unclear. The induction of beige adipocyte by rosiglitazone is blunted in Prdmknockdown cells, further indicating a role for Prdm16 in rosiglitazone-mediated WAT browning.

In a recent study, Moisan et al. JAK inhibitors can reduce lipid-droplet size, increase cellular oxygen consumption and increase Ucp1 expression in human adipocytes. These JAK inhibitor effects could be due to the repression and activation of the interferon and hedgehog signaling pathways, respectively.

Notch signaling is a critical pathway in the central nervous system. This pathway also plays an important role in metabolic regulation. Treatment with the chemical notch inhibitor DAPT has shown similar upregulation of brown fat-specific genes, including Ucp1, in cultured and primary adipocytes.

Injection of another notch inhibitor, DBZ, in leptin-deficient mice resulted in a reduction in body weight gain and improvement in metabolic parameters. Salsalate is a powerful anti-inflammatory drug originating from salicylates.

This drug has been traditionally used to reduce pain and inflammation. Its action can be explained by reducing inflammatory chemical signals such as TNF-α and IL Salsalate has also resulted in a reduction in body weight in preestablished obese mice, further suggesting its therapeutic potential in obesity.

Mechanistically, salsalate appears to modulate PKA activity in brown adipocytes. β3-Adrenergic receptor AR has a critical role in BAT activation and WAT browning through PKA-mediated signaling. Cyclic GMP has also been shown to be connected to metabolic processes in BAT via its roles in regulating mitochondrial activity.

Treatment with BAY 41— can sustain soluble guanylyl cyclase, reduce body fat mass and improve glucose metabolism in diet-induced obese mice. Accordingly, increased thermogenic adipocytes and higher levels of energy expenditure are observed in mice treated with BAY 41— The thermogenic activity of BAY 41— is mediated by the activation of lipid uptake in BATs and increased differentiation of brown adipocytes.

Dinitrophenol DNP is a proton ionophore that enables protons to cross mitochondrial membranes. In the past, DNP was widely used as a dieting aid.

However, it has been discontinued due to numerous side effects, including death in several patients. Serotonin is a monoamine neurotransmitter.

The role of serotonin and its related proteins in metabolism has also been widely investigated. Whole body or adipose tissue-specific deletion of Tph1, the enzyme that produces serotonin from its precursor tryptophan has protected mice from high-fat diet-induced obesity. Such an effect is due to an increased energy expenditure.

Consistently, mice injected with chemical inhibitors of Tph1 are also resistant to diet-induced obesity. Lactate is a well-known cellular metabolite produced in muscles during anaerobic glycolysis and high-intense activity. However, recent studies have revealed a new function of lactate in the browning effect.

Carrière et al. presented evidence showing that cold exposure can increase circulating lactate levels and induce monocarboxylate transporter Mct1 lactate importer gene expression in BAT and subcutaneous WAT. Exposure to lactate in adipocytes can stimulate mitochondrial activity, fatty acid oxidation and Ucp1 expression.

These metabolic effects of lactate are negated in the presence of Mct1 inhibitors, showing that lactate transport is important in lactate-mediated WAT browning. Exercise has been considered the best treatment for obesity and metabolic diseases.

Robert et al. These authors identified β-aminoisobutyric acid BAIBA as a key small-molecule myokine responsible for muscle-mediated WAT browning. BAIBA treatment in human cells can increase thermogenic gene expression, lipid oxidation and oxygen consumption rates. Consistently, BAIBA treatment in mice has decreased weight gain and improved glucose tolerance through a Pparα-mediated mechanism.

Inorganic nitrate is a cellular metabolite produced from NO oxidation. The effect of nitrate on WAT browning is dependent on the nitrate—nitrite—NO pathway and cyclic GMP signaling. Adenosine is an abundant ribonucleoside in the human body.

This ribonucleoside plays critical roles in energy transfer and signal transduction. Loss of adenosine receptor or treatment with adenosine antagonists has been shown to impair BAT-dependent thermogenesis, whereas activation of adenosine receptor prevents diet-induced obesity by inducing WAT browning and increasing energy expenditure.

Modern technologies in cell, molecular biology and genetic model systems have greatly advanced our understanding of the molecular mechanisms of cell biology, including brown adipocytes and WAT browning.

In addition, recent progress in the identification of chemical regulators has further suggested that BAT should be considered promising therapeutic targets for weight management and metabolic diseases.

Although recent studies have indicated that modulating energy expenditure by BAT or beige fat is highly effective in treating metabolic diseases, the significance of BAT in human physiology and unsolved issues for future therapeutic applications remain to be clarified.

Can brown fat in humans help increase energy expenditure beyond its role in maintaining body temperature? One of the main concerns is whether induction of browning in humans is a legitimate strategy against obesity and metabolic diseases.

It is clear that diet-, cold- and exercise-induced WAT browning and BAT activation in mice can prevent obesity and its associated metabolic diseases. However, this strategy has not yet been deemed attractive against human metabolic diseases. Systemic administration of catecholamines is negatively associated with human obesity; it is ineffective for human thermogenesis, with potential sympathomimetic effects.

This result is thought to be largely mediated by increased BAT activity. Are there any unwanted side effects of browning or increased BAT activity in humans?

WAT browning or increased BAT activity can protect animals from weight gain, and it can increase insulin resistance by enhancing energy expenditure and thermogenesis. As seen in DNP cases, increased uncoupling can also affect body temperature, free radical levels, injury risk and cellular metabolic rates.

Alternatively, to prevent any possible negative effects, temporal control of BAT activation could be used as an essential therapeutic intervention against metabolic diseases.

In addition, targeted delivery to adipocytes discussed below may be required to circumvent psychological and other effects on non-adipose tissues. Because currently available anti-obesity medications are often limited by their psychological or cardiovascular side effects, specific targeting of adipose tissue is needed to remove any potential side effects.

Most small molecules, including berberine, butein and β3-AR agonists, have shown effects on the neuronal system, thus suggesting that they might have unwanted actions on the cardiovascular system or neuronal tissues.

By increasing the concentration of the drugs in specific tissues, but not in others, targeted drug delivery can avoid the interaction of thermogenic small molecules with healthy tissues, thereby overcoming the downfalls of conventional methods of drug delivery.

Indeed, a recent discovery by the Langer group has shown that nanoparticle drug delivery methods targeting adipose tissues can be effective for obesity and insulin resistance without drug accumulation in other tissues. In addition, targeting CNS or mimicking outflow of PNS to activate brown fat or WAT browning can have therapeutic potential.

Autonomic hypothalamic innervation and peripheral temperature-sensitive neurons are involved in BAT activation and energy expenditure.

Cancer cachexia is an atrophy of muscle and adipose tissue in cancer patients. This condition can be easily observed in cancer patients and is one of the main causes of decreased survival rates and survival periods in cancer patients.

Neutralization of PTHrP in cancer-bearing mice has abrogated the WAT browning effect by cancer. Similar to PTHrP, anti-inflammatory treatments can also reduce the thermogenic activity of adipose tissues.

As such, current approaches for diminishing symptoms of cancer cachexia rely on anti-inflammatory treatments. In the future, more specific targets, such as PTHrP and IL-6, should be investigated to alleviate cancer cachexia.

Because numerous genetic factors and small molecules have been reported to have effects on WAT browning, approaches that reduce thermogenic adipocytes should be considered for cancer patients. How can we better and effectively activate BAT? With only a handful of thermogenic small molecules being available, a few immediate strategies can be used to achieve better treatment effects.

First, chemical modifications can be made to increase solubility, enhance targeted delivery, and improve controlled release. For instance, structure—activity relationship studies by chemical optimization can bring about thermogenic small molecules that are more effective against obesity and metabolic diseases.

For example, optimized sirtuin inhibitors based on resveratrol have been developed, and their efficacies have been tested in diabetic animals. Modifications, such as PEGylation, encapsulation with nanoparticles, and various other approaches executed for cancer, could also be applied for diabetes treatment.

Targeted delivery to regions, such as hypothalamic sites, brown adipose tissues, and white adipose tissues, can further reduce dosages and side effects in healthy tissues. This approach can also reduce the fluctuation of chemical levels in the circulation.

The field of drug delivery has advanced markedly in the past few decades. Collaboration is needed to increase the pharmacokinetics of thermogenic small molecules in the near future. Second, combinatorial compounds are currently being used for various diseases.

Combinatory treatments with two or more drugs with different mechanisms may thus increase the beneficial metabolic effects. For example, GLP-1 agonist, liraglutide, and melanocortin receptor agonist, RM, have been shown to have additive metabolic benefits in diet-induced obese mice.

The amounts of BAT, BMI, environments local temperatures, exercise, and food and genomes can vary widely among individuals. Therefore, unique approaches can be made for each patient.

To achieve this, improved diagnosis of BAT activation in humans preferably with non-invasive approaches and identification of biomarkers would be required to dissect the differences needed for personalized medicine. Finally, aside from focusing on the chemistry of small molecules, small molecules can also be used as tools to identify new molecular targets for therapeutic intervention and thus provide novel insights on the plasticity of adipocytes.

Using the same concept, PPARγ, MyoD and Sirt1 have been identified as molecular targets of a thiazolidinedione, suberanilohydroxamic acid and resveratrol, respectively. These molecules have been highlighted as targets for the therapeutic intervention of metabolic diseases and have offered novel insights into the biology of such diseases.

Likewise, the identification of Prdm4 by using butein also emphasizes the utility of small molecules in the better understanding BAT physiology.

Therefore, identification of better small molecules could provide new insights into thermogenic adipocytes. These molecules can thus be used as alternative therapeutic targets to develop interventions against obesity and metabolic dysregulation.

Recent studies of metabolism have focused on understanding the biology of BAT. This adipose tissue utilizes glucose and fatty acids as energy sources to burn calories and generate heat in response to cold exposure. However, further research is needed to reveal the significance of BAT and WAT browning in humans and its potential applications in human metabolic diseases.

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Thermogenic supplements are marketed as an easy way to Thermogenesks fat. While there is evidence that they can aents appetite and Reducing cholesterol naturally metabolism and fat burning, Thermogenesis and thermogenic agents effects are Thermogenesis and thermogenic agents small. Thermogenseis supplements contain Red pepper bruschetta ingredients Themogenesis to boost theemogenic metabolism and increase fat burning. Some of the most popular thermogenic supplements include caffeine, green tea, capsaicin and other plant extracts. This article reviews the most popular thermogenic supplements, their effectiveness, safety and side effects. When your body burns calories, it generates more heat, so supplements that boost metabolism or fat burning are considered thermogenic. Manufacturers claim that these supplements will help you lose weight or burn more body fat, but the veracity of this claim is hotly debated. Thank you for Thermogenezis tips for maintaining normal blood sugar. You are using a thetmogenic version with limited support for Thernogenic. To obtain Thermogenesis and thermogenic agents best agentx, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually.

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