Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation

Hull, Rebecca L.; Kodama, Keiichi; Utzschneider, Kristina M.; Carr, Darcy B.; Prigeon, Ronald L.; Kahn, Steven E.

doi:10.1007/s00125-005-1772-9

Cited by 140 publications

(119 citation statements)

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“…We have previously reported that mice overexpressing MCH manifest islet hyperplasia (18). To evaluate whether the converse effect, i.e., loss of MCH, leads to reduced ␤-cell mass, we examined MCH-KO mice under two conditions known to independently influence islet growth: genetic background (36,37) and high-fat feeding (38). Effect of genetic background on alterations in ␤-cell mass in MCH-KO mice.…”

Section: Resultsmentioning

confidence: 99%

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Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

et al. 2007

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Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide known to play a critical role in energy balance. We have previously reported that overexpression of MCH is associated with mild obesity. In addition, mice have substantial hyperinsulinemia and islet hyperplasia that is out of proportion with their degree of obesity. In this study, we further explored the role of MCH in the endocrine pancreas. Both MCH and MCHR1 are expressed in mouse and human islets and in clonal ␤-cell lines as assessed using quantitative real-time PCR and immunohistochemistry. Mice lacking MCH (MCH-KO) on either a C57Bl/6 or 129Sv genetic background showed a significant reduction in ␤-cell mass and complemented our earlier observation of increased ␤-cell mass in MCH-overexpressing mice. Furthermore, the compensatory islet hyperplasia secondary to a high-fat diet, which was evident in wild-type controls, was attenuated in MCH-KO. Interestingly, MCH enhanced insulin secretion in human and mouse islets and rodent ␤-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF)4␣, and HNF1␣. Together, these data provide novel evidence for an autocrine role for MCH in the regulation of ␤-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis. Diabetes 56:311-319, 2007 S everal neuropeptides that act in the central nervous system to regulate feeding behavior and energy homeostasis are also expressed in the enteric system as part of a potential hypothalamic-pancreatic axis (1). While some of these neuropeptides have an effect on exocrine pancreatic function, their effects on endocrine secretion are not fully understood. Thus, ghrelin, neuropeptide Y, galanin, orexins A and B, leptin, and the agouti gene product are neuropeptides that act in the hypothalamus to regulate feeding behavior and have also been reported to modulate islet function and/or growth (2-11). Melanin concentrating hormone (MCH) is another hypothalamic peptide that is known to regulate energy balance. A previous study reported that mice overexpressing MCH have islet hyperplasia, suggesting that MCH may also play a role in islet growth. However, the potential role of MCH and its receptors in the endocrine pancreas and a potential role of MCH in islet biology have not been explored.MCH is expressed in the lateral hypothalamus and zona incerta and has been shown to be important for feeding and energy homeostasis in rodents (12,13). MCH expression in the hypothalamus is upregulated by fasting and suppressed by leptin injection (13-15). Intracerebroventricular injections of MCH acutely stimulate feeding behavior (16). Mice lacking the prohormone are lean and hypophagic, whereas mice overexpressing MCH are obese (17,18). In rodents, MCH acts via a high-affinity G-proteincoupled receptor, designated MCH receptor (MCHR)1. In humans and primates, a second ...

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Section: Resultsmentioning

confidence: 99%

“…Most mouse models of obesity exhibit an islet compensatory response to maintain euglycemia in the face of insulin resistance (rev. in 37,38). To begin to dissect the dynamic effects of MCH on modulating ␤-cell mass, we fed MCH-KO mice and their wild-type littermates with a high-fat diet/ hypercaloric diet for 16 weeks.…”

Section: Resultsmentioning

confidence: 99%

Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

et al. 2007

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“…This notion is supported by the general observation that type 2 diabetes mellitus does not develop in most obese individuals or in pregnant women, who can have severe insulin resistance [3,7,8], due to a compensatory process involving increased beta cell function and notably beta cell mass expansion [3,[9][10][11].…”

Section: Introductionmentioning

confidence: 84%

Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein

et al. 2011

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Aims/hypothesis Irs2, which is upregulated by glucose, is important for beta cell plasticity. Cyclic AMP response element-binding protein (CREB) stimulates beta cell Irs2 expression and is a major calcium/calmodulin-dependent kinase (CaMK) IV target in neurons. We therefore hypothesised that CaMK IV mediates glucose-induced Irs2 expression in beta cells via CREB activation. Methods The functions of CaMK IV and CREB were investigated in MIN6 beta cells and mouse islets using the CaMK inhibitor KN62, the calcium chelator bapta-(AM) and the voltage-dependent calcium channel inhibitor nifedipine. Small interfering RNAs were used to silence endogenous CaMK IV production and expression vectors to overproduce constitutively active and dominant negative forms of CaMK IV and CREB. Irs1 and Irs2 expression were determined by quantitative PCR and Western blotting, and the role of CREB was also investigated by assessing its phosphorylation on serine 133.

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“…Several mechanisms could underlie the expansion of ␤-cells in this setting. First, ␤-cell replication can be driven by increased secretory demand placed upon the islet by dietary-fat-induced obesity and insulin resistance or chronic, mild hyperglycemia (24,25). Additionally, secreted factors such as hepatocyte growth factor or glucagon-like peptide-1 can induce ␤-cell replication (26 -28).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

Hogan

Ravnskjær

Matsumura

et al. 2015

Journal of Biological Chemistry

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Background: Loss of CRTC2 improves insulin sensitivity, but it is unknown if chronic CRTC2 activity causes hepatic insulin resistance. Results: Liver expression of constitutively active CRTC2 increased hepatic glucose production, despite compensatory increases in FOXO1 phosphorylation. Conclusion: Persistent increases in CRTC2 activation promote hepatic insulin resistance. Significance: Disrupting CREB signaling in liver could provide therapeutic benefit against insulin resistance.

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Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation

Abstract: Long-term fat feeding is associated with an increase in the beta cell population but an inadequate functional adaptation. Thus, a functional rather than a morphological abnormality appears to underlie dietary-fat-induced beta cell dysfunction.

Cited by 140 publications

References 59 publications

Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein

Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

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