Abstract
Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s) of adipose-PTP1B-deficiency on body mass and insulin resistance. To definitively establish the role of adipocyte-PTP1B in body mass regulation and glucose homeostasis, adipocyte-specific-PTP1B knockout mice (adip-crePTP1B−/−) were generated using the adiponectin-promoter to drive Cre-recombinase expression. Chow-fed adip-crePTP1B−/− mice display enlarged adipocytes, despite having similar body weight/adiposity and glucose homeostasis compared to controls. High-fat diet (HFD)-fed adip-crePTP1B−/− mice display no differences in body weight/adiposity but exhibit larger adipocytes, increased circulating glucose and leptin levels, reduced leptin sensitivity and increased basal lipogenesis compared to controls. This is associated with decreased insulin receptor (IR) and Akt/PKB phosphorylation, increased lipogenic gene expression and increased hypoxia-induced factor-1-alpha (Hif-1α) expression. Adipocyte-specific PTP1B deletion does not beneficially manipulate signaling pathways regulating glucose homeostasis, lipid metabolism or adipokine secretion in adipocytes. Moreover, PTP1B does not appear to be the major negative regulator of the IR in adipocytes.
Highlights
Caloric excess and a sedentary lifestyle are major contributors to epidemic obesity levels in Western society
Hematoxylin and eosin staining of epididymal adipose tissue sections revealed significant increases in adipocyte cell size in chow- and High-fat diet (HFD)-fed adip-crePTP1B2/2 mice compared with their respective controls (Figures 1F, G and H)
Despite only,50% reduction of Protein tyrosine phosphatase 1B (PTP1B) levels in white adipocytes, adipocyte protein 2 (aP2)-crePTP1B2/2 mice displayed significantly increased body weight on a HFD compared with PTP1Bfl/fl littermate controls [18]
Summary
Caloric excess and a sedentary lifestyle are major contributors to epidemic obesity levels in Western society. Obesity is associated with complex disorders, including cardiovascular disease and type 2 diabetes [1]. This rising burden of metabolic disease requires the development of new therapeutic strategies. White adipose tissue (WAT) is the main site for storage of excess energy from food intake, and plays a key role in sensing and coordinating adaptations in whole body glucose metabolism [2,3]. White adipose tissues function as endocrine and paracrine organs by secreting various adipokines. These bioactive molecules, including leptin, adiponectin, visfatin, omentin, tumor necrosis factor-a (TNF-a), resistin, retinol-binding protein 4 (RBP4) and many others influence metabolic processes such as food intake, glucose- and lipid-metabolism, inflammation and insulin resistance [4]. Insulin resistance precedes the development of type 2 diabetes, and is characterized by reduced insulin-dependent glucose uptake into muscle, adipose tissue and other insulin-sensitive peripheral tissues, inadequate suppression of hepatic glucose production, and accumulation of hepatic lipids [5]
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