ObjectiveInsulin signaling plays pivotal roles in the development and metabolism of many tissues and cell types. A previous study demonstrated that ablation of insulin receptor (IR) with aP2-Cre markedly reduced adipose tissues mass and protected mice from obesity. However, multiple studies have demonstrated widespread non-adipocyte recombination of floxed alleles in aP2-Cre mice. These findings underscore the need to re-evaluate the role of IR in adipocyte and systemic metabolism with a more adipose tissue-specific Cre mouse line.MethodsWe generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line.ResultsHere we show that the Adipoq-Cre-mediated IR KO in mice leads to lipodystrophy and metabolic dysfunction, which is in stark contrast to the previous study. In contrast to white adipocytes, absence of insulin signaling does not affect development of marrow and brown adipocytes, but instead is required for lipid accumulation particularly for the marrow adipocytes. Lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly, and impaired adipokine secretion.ConclusionsOur results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.

The intimate link between location of fat accumulation and metabolic disease risk and depot-specific differences is well established, but how these differences between depots are regulated at the molecular level remains largely unclear. Here we show that TRIP-Br2 mediates endoplasmic reticulum (ER) stress-induced inflammatory responses in visceral fat. Using in vitro, ex vivo and in vivo approaches, we demonstrate that obesity-induced circulating factors upregulate TRIP-Br2 specifically in visceral fat via the ER stress pathway. We find that ablation of TRIP-Br2 ameliorates both chemical and physiological ER stress-induced inflammatory and acute phase response in adipocytes, leading to lower circulating levels of inflammatory cytokines. Using promoter assays, as well as molecular and pharmacological experiments, we show that the transcription factor GATA3 is responsible for the ER stress-induced TRIP-Br2 expression in visceral fat. Taken together, our study identifies molecular regulators of inflammatory response in visceral fat that—given that these pathways are conserved in humans—might serve as potential therapeutic targets in obesity.

Background Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl transferase I from muscle (CPT1b) to increased liver (CPT1a) isoforms. Acutely increased CPT1a in normal rodent hearts has been shown to recapitulate the reduced fat oxidation and elevated ANP message of cardiac hypertrophy. Methods and Results Due to the potential for reduced fat oxidation to affect cardiac ANP thus induce adipose lipolysis, we studied peripheral and systemic metabolism in male C57BL/6 mice mouse model of transverse aortic constriction (TAC) in which LV hypertrophy occurred by 2 wk without functional decline until 16 wk (EF −45.6%; FS −22.6%). We report the first evidence for initially improved glucose tolerance (GT) and insulin sensitivity (IS) in response to 2 wks TAC vs SHAM, linked to enhanced insulin signaling in liver and visceral adipose tissue (eWAT), reduced white adipose (WAT) inflammation, elevated adiponectin, mulitilocular subcutaneous adipose tissue (iWAT) with upregulated oxidative/thermogenic gene expression, and downregulated lipolysis and lipogenesis genes in eWAT. By 6 wks TAC, the metabolic profile reversed with impaired IS and GT, reduced insulin signaling in liver, eWAT and heart, and downregulation of oxidative enzymes in brown adipose tissue and oxidative and lipogenic genes in iWAT. Conclusions Changes in insulin signaling, circulating natriuretic peptides and adipokines, and varied expression of adipose genes associated with altered insulin response/glucose handling and thermogenesis occurred prior to any functional decline in TAC hearts. The findings demonstrate multiphasic responses in extra-cardiac metabolism to pathogenic cardiac stress, with early iWAT browning providing potential metabolic benefits.