Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice

Abstract

The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat-like gene program and thermogenesis in subcutaneous adipose tissues. IntroductionThe rise in the incidence of obesity has driven a public health crisis because excess adiposity predisposes to cardiovascular disease, type 2 diabetes, hypertension, stroke, and many cancers (1, 2). Since weight gain is almost always caused by chronic energy imbalance, nonsurgical therapy for obesity must reduce energy intake and/or increase energy expenditure.There are 2 major types of adipose tissues in mammals, white and brown. White adipose tissue (WAT) is highly adapted to store excess energy in the form of triglycerides. Conversely, brown adipose tissue (BAT) oxidizes chemical energy to produce heat as a defense against hypothermia and obesity. WAT develops in distinct intra-abdominal depots and in the subcutaneous layer (between the fascia and muscle). The accumulation of intra-abdominal, visceral WAT, rather than total adiposity, is most strongly correlated with elevated risk for metabolic dysfunction and cardiovascular disease (3-8). By contrast, expansion of subcutaneous WAT, even in the setting of obesity, has been suggested to promote insulin sensitivity in rodents and humans (9)(10)(11)(12)(13)(14). Implantation of subcutaneous WAT, but not visceral WAT, into the abdominal cavity of mice improves whole-body metabolism (15, 16). Moreover, subcutaneous and visceral WAT express unique gene signatures (17). These data suggest that some of the distinct metabolic effects of subcutaneous and visceral WAT are cell autonomous. However, the ...

High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

“…50,51 With respect to cell-autonomous inducibility of molecular pathways of brown fat adipogenesis, it has been shown that mRNA expression of Prdm16 is higher in inguinal than epididymal fat pads in B6 mice, and that adipose tissue overexpression of Prdm16 on this genetic background results in emergence of brown-like adipocytes in inguinal but not in epididymal fat pads. 18 The retroperitoneal and inguinal fat pads (but not epididymal fat pads to our knowledge) showed emergence of brown fat (in response to cold or b 3 -stimulation) in several previous studies. 22,45,53 Some of these studies indicated that the capacity for brown fat adipogenesis in WAT depends largely on genetic Figure S5).…”

“…Finally, we observed a significant upregulation of Prdm16 in this tissue in HFD compared with ND rats; this is in agreement with a recent study demonstrating that PRDM16 overexpression in WAT results in emergence of brown-like adipocytes in this tissue. 18 In this study, we observed that mRNA expression of Adrb3 in retroperitoneal fat was significantly higher in HFD than ND rats. Upregulation of Adrb3 is consistent with previous research demonstrating that adrenergic stimulation 8 via the b 3 -adrenergic receptor has a key role in brown fat activation and subsequent energy dissipation, 8 as well as emergence of brown fat in WAT.…”

“…The reason for this fat-pad variation is not entirely clear, however, a likely explanation is that fat-pads differ in the density of sympathetic innervation 50,51 and/or cell-autonomous inducibility of molecular pathways of brown fat adipogenesis. 18 Supporting the former, it has been shown that the number of sympathetic nerve fibers correlates positively with the density of brown adipocytes in WAT 52 and that norepinephrine concentration varies among fat pads, being higher, for example, in retroperitoneal than epididymal fat pads in Siberian hamsters. 50,51 With respect to cell-autonomous inducibility of molecular pathways of brown fat adipogenesis, it has been shown that mRNA expression of Prdm16 is higher in inguinal than epididymal fat pads in B6 mice, and that adipose tissue overexpression of Prdm16 on this genetic background results in emergence of brown-like adipocytes in inguinal but not in epididymal fat pads.…”

“…Previous studies found brown fat emergence in WAT coupled with enhanced whole-body energy expenditure, but these studies used non-dietary manipulations, including chronic exposure to cold, treatment with b3-adrenergic receptor agonists and forced WAT overexpression of key molecules of brown fat adipogenesis/function, such as PGC-1a, UCP1 or PRDM16. 12,14,18,20,[39][40][41][42] Brown fat adipogenesis has recently gained the interest of many research groups, as compelling evidence has been provided that brown fat exists not only in human neonates, as thought originally, but also in human adults where it likely protects against obesity, 2-8 through its superior capacity for burning fat (both stored and eaten) and energy dissipation. 9,43 Substantial progress in our understanding of brown fat adipogenesis has been made recently (Seale et al 43 ).…”

“…12,13 Importantly, the presence of these brownlike adipocytes in WAT, even in very small quantities, is associated with a significant reduction in whole-body adiposity. 14 Despite the recent advances in understanding brown fat adipogenesis, [15][16][17][18] the molecular mechanisms of brown fat emergence in traditional WAT have yet to be elucidated. A complex network of transcription factors that includes peroxisome proliferator-activated receptor-g coactivator1a (PGC-1a) controls brown fat adipogenesis.…”