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 3

Increase in islet size and β cell mass and enhanced expression of insulin signaling proteins in islets of pancreas-ObR-KO mice.

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Increase in islet size and β cell mass and enhanced expression of insuli...
(A) H&E staining or immunofluorescence staining for insulin and glucagon in pancreas sections of ObRlox and KO mice. Scale bars: 100 μm. (B) β Cell mass estimated by morphometric analysis. *P < 0.05 versus ObRlox; n = 4. (C) Immunofluorescence staining for insulin and β-catenin in pancreas sections to determine β cell size. Relative β cell size (mean from n ≥ 200 cells counted) is shown in the graph. *P < 0.05 versus ObRlox; mean ± SEM, n = 3. Scale bars: 10 μm. (D) Western blots of total islet lysates for p-Akt (Ser473), Akt, p-p70S6K (Thr389), p70S6K, p-FoxO1 (Ser256), FoxO1, and α-tubulin as a loading control. The relative expression of p-Akt, p-p70S6K, and p-FoxO1 normalized to each total protein is shown in the graph. *P < 0.05 versus ObRlox; n = 4–6. (E) Immunofluorescence for Glut-2 and insulin in pancreas sections of ObRlox and KO mice. Scale bars: 50 μm. Western blots of total islet lysates for Glut-2 (E, lower panel), p-PTEN, and PTEN (F), normalized to α-tubulin. The relative expression of p-PTEN normalized to α-tubulin is shown in the graph. *P < 0.05 versus ObRlox; n = 4. (G) Expression of SOCS-3 and preproinsulin in ObRlox and KO islets assessed by quantitative real-time PCR. *P < 0.05 versus ObRlox; n = 4–6. Data were obtained from pancreas or islet samples from 4- to 6-month-old mice and are shown as mean ± SEM.