https://www.mergenmetz.nl/menn/wp-content/uploads/2012/07/Insirine-of-bewegen-artikel-in-Cell.pdf

Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human

Brown fat can increase energy expenditure and protect against obesity through a specialized program of uncoupled respiration. Here we show by in vivo fate mapping that brown, but not white, fat cells arise from precursors that express Myf5, a gene previously thought to be expressed only in the myogenic lineage. We also demonstrate that the transcriptional regulator PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16) controls a bidirectional cell fate switch between skeletal myoblasts and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of PRDM16 in myoblasts induces their differentiation into brown fat cells. PRDM16 stimulates brown adipogenesis by binding to PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function. Finally, Prdm16-deficient brown fat displays an abnormal morphology, reduced thermogenic gene expression and elevated expression of muscle-specific genes. Taken together, these data indicate that PRDM16 specifies the brown fat lineage from a progenitor that expresses myoblast markers and is not involved in white adipogenesis.

PRDM16 controls a brown fat/skeletal muscle switch

Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.

/pdf/brown-and-beige-fat-development-function-and-therapeutic-5dt1btf02v.pdf

Brown and beige fat: development, function and therapeutic potential

Objective: The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents, but have been controversial in man. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans, and to clarify the effects of cold exposure and adiposity. Research Design and Methods: In vivo 2-[ 18 F ]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 males and 25 females) aged 23 - 65 y by positron emission tomography (PET) combined with X-ray computed tomography (CT). Results: When exposed to cold (19 °C) for 2 hr, 17 out of 32 younger subjects (23-35 y.o.) and 2 out of 24 elderly subjects (38-65 y.o.) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept in warm (27 °C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared to summer (p Conclusions: Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans, and suggest a role in the control of body temperature and adiposity.

https://diabetes.diabetesjournals.org/content/diabetes/58/7/1526.full.pdf

High Incidence of Metabolically Active Brown Adipose Tissue in Healthy Adult Humans: Effects of Cold Exposure and Adiposity

Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.

/pdf/fgf21-regulates-pgc-1a-and-browning-of-white-adipose-tissues-1in9r4r2j7.pdf

FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis

Brown adipocytes are thermogenic cells which play an important role in energy balance. Their thermogenic activity is due to the presence of a mitochondrial uncoupling protein (UCP). Until recently, it was admitted that in rodents brown adipocytes were mainly located in classical brown adipose tissue (BAT). In the present study, we have investigated the presence of UCP protein or mRNA in white adipose tissue (WAT) of rats. Using polymerase chain reaction or Northern blot hybridization, UCP mRNA was detected in mesenteric, epidydimal, retroperitoneal, inguinal and particularly in periovarian adipose depots. The uncoupling protein was detected by Western blotting in mitochondria from periovarian adipose tissue. When rats were submitted to cold or to treatment with a beta-adrenoceptor agonist, UCP expression was increased in this tissue as in typical brown fat. Moreover, the expression was decreased in obese fa/fa rats compared to lean controls. Morphological studies showed that periovarian adipose tissue of rats kept at 24 degrees C contained cells with numerous typical BAT mitochondria with or without multilocular lipid droplets. Immunocytochemistry confirmed that multilocular cells expressed mitochondrial UCP. Furthermore, the number of brown adipocytes and the density of mitochondrial cristae increased in parallel with exposure to cold. These results demonstrate that adipocytes expressing UCP are present in adipose deposits considered as white fat. They suggest the existence of a continuum in rodents between BAT and WAT, and a great plasticity between adipose tissue phenotypes. The physiological importance of brown adipocytes in WAT and the regulation of UCP expression remain open questions.

S. Raimbault

Papers

Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization.