Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver

Abstract

Obesity is typically associated with resistance to leptin, yet the mechanism by which leptin signaling becomes impaired is poorly understood. Here we sought to determine if the development of obesity and leptin resistance correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) in peripheral tissues and whether over-expression of this phosphatase, specifically in liver, could alter the leptin-mediated effects on feeding and glucose metabolism. Obesity was induced in mice through a high-fat diet that resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia. Resistance to leptin was confirmed as exogenous leptin administration reduced food intake in animals on low-fat, but not high-fat diets. Diet-induced resistance to leptin and insulin was associated with increased hepatic levels of PTP1B. Intriguingly, hepatic adenoviral over-expression of PTP1B in ob/ob mice attenuated the ability of exogenous leptin to reduce both plasma glucose levels and food intake. These findings suggest that leptin reduces both plasma glucose and food intake in part through actions on the liver, and hepatic leptin resistance resulting from over-expression of PTP1B may contribute to the development of both diabetes and obesity.

Role of leptin in the pancreatic β-cell: effects and signaling pathways

“…Conversely, no proliferative action of leptin has been found in experiments with islets from adult rats (Okuya et al 2001). Recent studies with disruption of the leptin receptor either in the pancreas (Morioka et al 2007) or in b-cells and hypothalamus (Covey et al 2006) indicate that leptin may have a negative role in b-cell mass expansion, since the average size of the islets from these KO mice was found to be increased. In one of these studies, no modification of proliferation was observed (Morioka et al 2007).…”

“…Both proteins work as negative regulators of leptin-induced activation of the JAK/STAT pathway (Morris & Rui 2009). In addition to central leptin resistance, several studies on obesity models have observed attenuated leptin signaling in peripheral tissues (Prpic et al 2003, Lam et al 2006, Steinberg et al 2006, Nave et al 2008. In most cases, an increase in PTP1B or SOCS3 levels was associated with this attenuated response to leptin.…”

“…Numerous in vivo and in vitro studies have shown that this hormone activates a diversity of events in the b-cell, which will be reviewed in the next sections. Additionally, experiments in knockout (KO) mice with specific deletion of the leptin receptor in the pancreas or in the b-cell and the hypothalamus have shown alterations in glucose homeostasis as well as in b-cell function and mass in these animals (Covey et al 2006, Morioka et al 2007. Leptin signaling defects in b-cells lacking the leptin receptor lead to hyperinsulinemia, which develops prior to insulin resistance (Gray et al 2010).…”

“…Three tyrosine residues, whose phosphorylation is important for leptin signaling, are indicated in ObRb: Y985 interacts with the SH2-containing protein tyrosine phosphatase 2, Y1077 with STAT5, and Y1138 with STAT3. specific disruption of the Obr(Lepr) gene either in the pancreas or in the b-cell and hypothalamus (Covey et al 2006, Morioka et al 2007.…”

“…In most cases, an increase in PTP1B or SOCS3 levels was associated with this attenuated response to leptin. In the case of the endocrine pancreas, it has been proposed that leptin resistance in the b-cell may alter its function and could contribute to diabetes in obese individuals (Seufert 2004, Covey et al 2006, Morioka et al 2007). Since leptin signaling in the pancreatic b-cell triggers similar pathways as those activated in the hypothalamus or other tissues, it would be interesting to explore whether leptin resistance occurs in the b-cell during obesity and the mechanisms involved.…”