Disruption of leptin receptor expression in the pancreas directly affects β cell growth and function in mice

Abstract

Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on β cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater β cell mass secondary to increased β cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 β cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes. IntroductionThe factors that promote β cell failure and increase the incidence of diabetes in obese individuals are not fully understood. The presence of hyperglycemia and hyperphagia in obese individuals, despite the presence of high levels of circulating insulin and leptin, suggests these individuals are resistant to the actions of both hormones (1). The hypothalamic actions of leptin are relatively well characterized; however, the expression of the long form of the leptin receptor (ObRb) in peripheral tissues, including the endocrine pancreas, indicates that leptin can also exert peripheral actions independent of its effects in the hypothalamus (2). For example, in vitro studies have reported inhibitory effects of leptin on insulin gene expression and insulin secretion in β cell lines and isolated murine and human islets (2-4). Furthermore, leptin treatment of ob/ob mice reversed hyperinsulinemia (5). Although the db/db mouse, which carries a mutation in the ObR gene (6), manifests hyperinsulinemia and hyperplastic islets (7), it is unclear whether the alterations in islet growth and function in db/db mice are due to a lack of direct leptin action in β cells or secondary to the effects of insulin resistance in peripheral tissues.To directly assess the role of leptin signaling in the pancreas, we used the Cre-loxP technique to create a mouse model that is

Reporter islets in the eye reveal the plasticity of the endocrine pancreas

“…The lack of leptin signaling is a likely contributor to this volume expansion. Indeed, using pancreas-specific leptin receptor KO mice, it has been shown that the disruption of leptin action in islets results in enhanced PI3K/AKT signaling, associated with increases in beta cell size and islet mass (17). Although this compensatory islet growth has been demonstrated in vitro, we are now able to verify this pattern in the living ob/ob mouse longitudinally through the analysis of single reporter islets.…”

MECHANISMS IN ENDOCRINOLOGY: The endocrine role of the skeleton: background and clinical evidence

“…Thereby, insulin secretion was decreased (26). Additionally, leptin acted directly on b-cells to block the secretion of insulin (28,29). Of note, by enhancing bone resorption, the active, undercarboxylated form of OC is indirectly released (Fig.…”

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

“…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.…”