Protein Tyrosine Phosphatase Epsilon Affects Body Weight by Downregulating Leptin Signaling in a Phosphorylation-Dependent Manner

Abstract

Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation.

BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis

“…With noradrenergic stimulation, the foci were thought to involve direct transformation of adult white adipocytes (42)(43)(44) or de novo differentiation of committed brown adipocytes (45). It should also be noted that manipulation of certain genes that increased mitochondrial biogenesis in white adipocytes resulted in improved energy metabolism (18)(19)(20)46). Likewise, overexpression of BMP4 in WAT promoted mitochondrial biogenesis as well as the expression of genes required for glucose and lipid metabolism, including Glut4, Pck-1, MCAD, and CPT1b (Fig.…”

“…Moreover, the number of BAT-like cells is inversely correlated with body mass index (BMI) in humans (17). Identification of the factors that induce brown-like fat cells in WAT could provide an approach for the prevention and/or treatment of obesity and its metabolic complications.Recently, mouse models have become available with specific genetic manipulations that produce a lean phenotype with lower WAT mass and enhanced insulin sensitivity (18)(19)(20). The WAT of these mice possesses some characteristics of BAT, notably increased mitochondrial biogenesis and metabolic rate.…”

“…Recently, mouse models have become available with specific genetic manipulations that produce a lean phenotype with lower WAT mass and enhanced insulin sensitivity (18)(19)(20). The WAT of these mice possesses some characteristics of BAT, notably increased mitochondrial biogenesis and metabolic rate.…”

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

“…To date only a handful of protein tyrosine phosphatases (PTPs) have been implicated in leptin signaling, including SHP-2 that links LEPR-B to the Ras/MAPK pathway [49,50], PTP1B [49,[51][52][53][54] and PTPε [55] that dephosphorylate JAK2, TCPTP [56] that dephosphorylates STAT3 [56], and phosphatase and tensin homologue (PTEN) [57] that attenuates PI3K signaling (Figure 3). Here we will focus on the roles of PTP1B and TCPTP since their elevated hypothalamic expression has been implicated in leptin resistance and dietinduced obesity [51,56,58].…”

Adaptor Protein GRB2 Promotes Src Tyrosine Kinase Activation and Podosomal Organization by Protein-tyrosine Phosphatase ϵ in Osteoclasts

“…The central role of C-terminal phosphorylation of PTPe is evident also in other, non-bone settings. Phosphorylation of the receptor-type form of PTPe (RPTPe) at the analogous residue Tyr-695 is required for activation of Src downstream of ErbB2/Neu in mouse mammary tumors (10,11) and for inhibition of JAK2 downstream of the activated leptin receptor in hypothalamic neurons (12). C-terminal phosphorylation of cyt-PTPe by the activated EGF receptor drives the phosphatase to associate with microtubules and inhibits its activity (13).…”