Disruption of leptin receptor expression in the pancreas directly affects β cell growth and function in mice
Tomoaki Morioka, … , Robert T. Kennedy, Rohit N. Kulkarni
Tomoaki Morioka, … , Robert T. Kennedy, Rohit N. Kulkarni
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2860-2868. https://doi.org/10.1172/JCI30910.
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Research Article

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.

Authors

Tomoaki Morioka, Esra Asilmaz, Jiang Hu, John F. Dishinger, Amarnath J. Kurpad, Carol F. Elias, Hui Li, Joel K. Elmquist, Robert T. Kennedy, Rohit N. Kulkarni

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Figure 2

Improved glucose tolerance and enhanced early-phase insulin secretion in pancreas-ObR-KO mice.

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Improved glucose tolerance and enhanced early-phase insulin secretion in...
(A) Plasma insulin levels after an i.p. injection of glucose (3 g/kg body weight) to evaluate acute-phase insulin secretion in 6-month-old ObRlox and KO mice. *P < 0.05 versus ObRlox controls. n = 6. (B) Blood glucose after i.p. injection of glucose (2 g/kg body weight) in 6-month-old male and female ObRlox and KO mice. *P < 0.05 versus ObRlox controls; n = 6–7. Plasma insulin (C) and blood glucose (D) levels after overnight fasting in 6-month old male and female ObRlox and KO mice. *P < 0.05 versus ObRlox controls; n = 6. (E) Percent change in blood glucose after i.p. injection of insulin (1 U/kg body weight) in 6-month-old male ObRlox and KO mice. n = 7; P = NS. Data are shown as mean ± SEM. Representative traces of intracellular Ca2+ flux (F) and insulin secretion (G) measured in primary size-matched islets isolated from 6-month-old male ObRlox and KO mice with or without 100 nM (F) or 10 nM (G) leptin. For area under the curve (AUC), P < 0.05, ObRlox versus KO mice in each case; P < 0.05, vehicle versus leptin+ in ObRlox mice for both Ca2+ and insulin; P = NS for vehicle versus leptin+ in KO mice for both Ca2+ and insulin. n = 6 islets from 3 individual mice in each group.