Adipocyte-Specific Protein Tyrosine Phosphatase 1B Deletion Increases Lipogenesis, Adipocyte Cell Size and Is a Minor Regulator of Glucose Homeostasis

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.

Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B

“…As with other mouse models of PTP1B-specific deletion [7,10,11] body weight, body fat and bone mineral density of the female liver-specific PTP1B knockout mice did not differ from control mice. This is the first examination of the body weight phenotype in liver-specific PTP1B knockout animals in females and reveals that there is no sexual dimorphism in body weight regulation in these animals.…”

Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation

“…However, if the observed weight gain is caused only by adipose-specific PTP1B deficiency remains to be determined because the aP2 promoter can delete the target gene in other cell types (51,52). Indeed, adipose-specific PTP1B KO mice generated using the adiponectin promoter exhibit comparable body weight to controls when fed an HFD but display larger adipocytes and increased basal lipogenesis (20). These studies identify PKM2 as one of several PTP1B substrates that can mediate PTP1B functions in adipose tissue.…”

“…However, the role of PTP1B in adipocytes is unresolved, with studies demonstrating detri-* This work was supported, in whole or in part, by National Institutes of Health 1 Both authors contributed equally to this work. 2 mental or beneficial effects of adipose PTP1B deficiency on body mass and insulin sensitivity (19,20). Notably, PTP1B is a modulator of brown fat adipogenesis through a peroxisome proliferator-activated receptor ␥-dependent mechanism, and PTP1B deficiency regulates PKR-like endoplasmic reticulumregulated kinase phosphorylation and protein synthesis (21)(22)(23).…”

Myeloid-Cell Protein Tyrosine Phosphatase-1B Deficiency in Mice Protects Against High-Fat Diet and Lipopolysaccharide-Induced Inflammation, Hyperinsulinemia, and Endotoxemia Through an IL-10 STAT3-Dependent Mechanism

“…Evidence to support the notion that PTP1B inhibition may be beneficial in states of overnutrition and insulin resistance was demonstrated in mice with a global-(1,2) as well as tissue-specific PTP1B deletion (3)(4)(5)(6).…”

“…Tail-blood glucose from fasted (5 h) mice was measured using glucometers (Accu-Chek, Burgess Hill, U.K.) (6). Serum TNF-a, IL-6, monocyte chemoattractant protein-1, insulin, leptin, plasminogen activator inhibitor-1, and resistin were measured using adipokine multiplex kit (Millipore, U.K.), and serum IL-10 levels were determined by ELISA (R&D Systems, Minneapolis, MN).…”