Acquirement of Brown Fat Cell Features by Human White Adipocytes

Abstract

Obesity, i.e. an excess of white adipose tissue (WAT), predisposes to the development of type 2 diabetes and cardiovascular disease. Brown adipose tissue is present in rodents but not in adult humans. It expresses uncoupling protein 1 (UCP1) that allows dissipation of energy as heat. Peroxisome proliferator-activated receptor ␥ (PPAR␥) and PPAR␥ coactivator 1␣ (PGC-1␣) activate mouse UCP1 gene transcription. We show here that human PGC-1␣ induced the activation of the human UCP1 promoter by PPAR␥. Adenovirus-mediated expression of human PGC-1␣ increased the expression of UCP1, respiratory chain proteins, and fatty acid oxidation enzymes in human subcutaneous white adipocytes. Changes in the expression of other genes were also consistent with brown adipocyte mRNA expression profile. PGC-1␣ increased the palmitate oxidation rate by fat cells. Human white adipocytes can therefore acquire typical features of brown fat cells. The PPAR␥ agonist rosiglitazone potentiated the effect of PGC-1␣ on UCP1 expression and fatty acid oxidation. Hence, PGC-1␣ is able to direct human WAT PPAR␥ toward a transcriptional program linked to energy dissipation. However, the response of typical white adipocyte targets to rosiglitazone treatment was not altered by PGC-1␣. UCP1 mRNA induction was shown in vivo by injection of the PGC-1␣ adenovirus in mouse white fat. Alteration of energy balance through an increased utilization of fat in WAT may be a conceivable strategy for the treatment of obesity.

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

“…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 ).…”

HSV vector-mediated transduction and GDNF secretion from adipose cells

“…17 Adenoviral-mediated gene transfer has also been demonstrated in differentiated adipocytes in vitro 18 and following adipose tissue injection in vivo, with transgene expression persisting for approximately 2 weeks. [19][20][21][22] However, preadipocytes of either human or murine origin were not transduced unless either very high multiplicities were applied or the cells were modified to express the coxsackie-adenovirus receptor (CAR) normally lacking on the surface of preadipocytes. 22,23 In contrast, retroviral-mediated transduction is limited to replicating preadipocytes, while nondividing adipocytes are not infected.…”

“…[19][20][21][22] However, preadipocytes of either human or murine origin were not transduced unless either very high multiplicities were applied or the cells were modified to express the coxsackie-adenovirus receptor (CAR) normally lacking on the surface of preadipocytes. 22,23 In contrast, retroviral-mediated transduction is limited to replicating preadipocytes, while nondividing adipocytes are not infected. 24 After cell transduction, the HSV genome persists as an intranuclear episomal element, 25 eliminating risks related to insertional mutagenesis.…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…Indeed, when studied under the conditions of the above treatments, AMPK in WAT and other tissues was found to be activated (Jelenik et al 2010;Kopecky et al 2009;Orci et al 2004;Ye et al 2006). Concerning the mechanism of energy expenditure induced by the treatments, mitochondrial uncoupling mediated by UCP1 in WAT adipocytes (Orci et al 2004;Tiraby et al 2003;Petrovic et al 2010;Collins et al 1997;Guerra et al 1998;Himms-Hagen et al 2000) could be involved in most of the cases. Further studies are required to learn more about the mechanisms underlying the induction of energy dissipating adipocytes in response to treatments inducing UCP1 in adipose tissue.…”

“…Thus, treatment using leptin (Orci et al 2004), PPARa agonists (Ribet et al 2010), adrenoreceptor agonists and lipolytic agents (Granneman et al 2003;Yehuda-Shnaidman et al 2010), dietary n-3 polyunsaturated fatty acids (Jelenik et al 2010;Kopecky et al 2009;Flachs et al 2005), and thiazolidinediones acting as specific agonists of PPARc [TZD; (Tiraby et al 2003;Wilson-Fritch et al 2004;Petrovic et al 2010)] resulted in reduced adiposity and metabolic disturbances related to obesity, observed mostly under the conditions of high-fat feeding in obesity-prone C57BL/6 mice. Importantly, lipid catabolism in WAT was always up-regulated, and in situ lipogenesis in WAT was suppressed (Orci et al 2004;Ribet et al 2010;Flachs et al 2005;Tiraby et al 2003;Wilson-Fritch et al 2004), suggesting activation of AMPK Genes Nutr (2012) 7:369-386 381 in response to decreased energy status in WAT. Indeed, when studied under the conditions of the above treatments, AMPK in WAT and other tissues was found to be activated (Jelenik et al 2010;Kopecky et al 2009;Orci et al 2004;Ye et al 2006).…”