Hepatic leptin signalling and subdiaphragmatic vagal efferents are not required for leptin-induced increases of plasma IGF binding protein-2 (IGFBP-2) in ob/ob mice

Levi, Jasna; Huynh, Frank K.; Denroche, Heather C.; Neumann, Ursula; Glavas, Maria M.; Covey, Scott D.; Kieffer, Timothy J.

doi:10.1007/s00125-011-2426-8

Cited by 24 publications

(27 citation statements)

References 49 publications

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“…The clarifi cation of these questions will require investigation of the different cell types of the liver in their physiological tissue context. In agreement with our observations, the hepatocyte-specifi c deletion of LepR in ob / ob mice did not preclude the ability of infused leptin to increase the circulating levels of insulin-like growth factor binding protein-2 (IGFBP2), a leptin-regulated liver product possibly implicated in leptin metabolic actions ( 66 ). Thus, a more complete understanding of the metabolic role of leptin in AGPAT2-defi cient mice will require the generation of a total liver-specifi c leptin receptor knockout mouse.…”

Section: Discussionsupporting

confidence: 89%

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Cortés

Cautivo

Rong

et al. 2014

Journal of Lipid Research

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Section: Discussionsupporting

confidence: 89%

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Cortés

Cautivo

Rong

et al. 2014

Journal of Lipid Research

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“…S1). Interestingly, this pattern was restored when ob/ob mice were treated with leptin for 4 d (2 μg/d) (15) (Fig. 1B and Fig.…”

Section: Resultsmentioning

confidence: 86%

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

Park

Ryu²,

Yu³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

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Leptin is a pivotal regulator of energy and glucose homeostasis, and defects in leptin signaling result in obesity and diabetes. The ATP-sensitive potassium (K ATP ) channels couple glucose metabolism to insulin secretion in pancreatic β-cells. In this study, we provide evidence that leptin modulates pancreatic β-cell functions by promoting K ATP channel translocation to the plasma membrane via AMP-activated protein kinase (AMPK) signaling. K ATP channels were localized mostly to intracellular compartments of pancreatic β-cells in the fed state and translocated to the plasma membrane in the fasted state. This process was defective in leptin-deficient ob/ob mice, but restored by leptin treatment. We discovered that the molecular mechanism of leptin-induced AMPK activation involves canonical transient receptor potential 4 and calcium/calmodulindependent protein kinase kinase β. AMPK activation was dependent on both leptin and glucose concentrations, so at optimal concentrations of leptin, AMPK was activated sufficiently to induce K ATP channel trafficking and hyperpolarization of pancreatic β-cells in a physiological range of fasting glucose levels. There was a close correlation between phospho-AMPK levels and β-cell membrane potentials, suggesting that AMPK-dependent K ATP channel trafficking is a key mechanism for regulating β-cell membrane potentials. Our results present a signaling pathway whereby leptin regulates glucose homeostasis by modulating β-cell excitability.T he K ATP channel, an inwardly rectifying K + channel that consists of pore-forming Kir6.2 and regulatory sulfonylurea receptor 1 (SUR1) subunits (1), functions as an energy sensor: its gating is regulated mainly by the intracellular concentrations of ATP and ADP. In pancreatic β-cells, K ATP channels are inhibited or activated in response to the rise or fall in blood glucose levels, leading to changes in membrane excitability and insulin secretion (2, 3). Thus, K ATP channel gating has been considered an important mechanism in coupling blood glucose levels to insulin secretion. Recently, trafficking of K ATP channels to the plasma membrane was highlighted as another important mechanism for regulating K ATP channel activity (4-6).AMP-activated protein kinase (AMPK) is a key enzyme regulating energy homeostasis (7). We recently demonstrated that K ATP channels are recruited to the plasma membrane in glucosedeprived conditions via AMPK signaling in pancreatic β-cells (6). Inhibition of AMPK signaling significantly reduces K ATP currents, even after complete wash-out of intracellular ATP (6). Given these results, we proposed a model that recruitment of K ATP channels to the plasma membrane via AMPK signaling is crucial for K ATP channel activation in low-glucose conditions. However, the physiological relevance of this model remains unclear because pancreatic β-cells had to be incubated in media containing less than 3 mM glucose to recruit a sufficient number of K ATP channels to the plasma membrane (6). We thus hypothesized that there should be an e...

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“…We treated leptin receptor-deficient db/db mice with AdLepr-b, which confers liver-selective expression 18 and restores phospho-STAT3 signaling in the liver. 16 Upon treatment with Ad-Lepr-b, the db/db mice remained obese and hyperinsulinemic (Supporting Fig. 2).…”

Section: Resultsmentioning

confidence: 95%

A Role for Hepatic Leptin Signaling in Lipid Metabolism via Altered Very Low Density Lipoprotein Composition and Liver Lipase Activity in Mice

et al. 2013

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Obesity is highly associated with dyslipidemia and cardiovascular disease. However, the mechanism behind this association is not completely understood. The hormone leptin may be a molecular link between obesity and dysregulation of lipid metabolism. Leptin can affect lipid metabolism independent of its well-known effects on food intake and energy expenditure, but exactly how this occurs is ill-defined. We hypothesized that since leptin receptors are found on the liver and the liver plays an integral role in regulating lipid metabolism, leptin may affect lipid metabolism by acting directly on the liver. To test this hypothesis, we generated mice with a hepatocyte-specific loss of leptin signaling. We previously showed that these mice have increased insulin sensitivity and elevated levels of liver triglycerides compared with controls. Here, we show that mice lacking hepatic leptin signaling have decreased levels of plasma apolipoprotein B yet increased levels of very low density lipoprotein (VLDL) triglycerides, suggesting alterations in triglyceride incorporation into VLDL or abnormal lipoprotein remodeling in the plasma. Indeed, lipoprotein profiles revealed larger apolipoprotein B-containing lipoprotein particles in mice with ablated liver leptin signaling. Loss of leptin signaling in the liver was also associated with a substantial increase in lipoprotein lipase activity in the liver, which may have contributed to increased lipid droplets in the liver. Conclusion: Lack of hepatic leptin signaling results in increased lipid accumulation in the liver and larger, more triglyceride-rich VLDL particles. Collectively, these data reveal an interesting role for hepatic leptin signaling in modulating triglyceride metabolism. (HEPATOLOGY 2013;57:543-554) D espite the well-accepted link between obesity, diabetes, and dyslipidemia, the molecular mechanisms that drive this association are not understood. The hormone leptin is a potential link between obesity and abnormal lipid metabolism. Leptin is secreted from adipose tissue and acts on the hypothalamus to reduce food intake and increase energy expenditure.1,2 Thus, leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are hyperphagic and obese. However, these mice also display hypertriglyceridemia, 3 hypercholesterolemia, 3 hepatic steatosis, 4 and impaired lipid tolerance. 5 Several studies suggest that these effects on lipid metabolism are independent of leptin's effects on food intake and obesity. For example, restricting food intake in ob/ob mice cannot improve lipid metabolism as effectively as leptin treatment. 6,7 In addition, lipodystrophic mice and humans, which have little to no adipose tissue and are hypoleptinemic, also display hyperlipidemia and hepatic steatosis, and these symptoms are ameliorated by leptin. 8,9 Clearly, leptin has effects on lipid metabolism independent of its effects on body weight.The manner by which leptin directly affects lipid metabolism is not well understood. We hypothesized Abbreviations: Ad-b-gal, adenovirus exp...

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Hepatic leptin signalling and subdiaphragmatic vagal efferents are not required for leptin-induced increases of plasma IGF binding protein-2 (IGFBP-2) in ob/ob mice

Abstract: Taken together, these data indicate that hepatic leptin signalling and subdiaphragmatic vagal inputs are not required for leptin upregulation of plasma IGFBP-2 nor blood glucose lowering in ob/ob mice.

Cited by 24 publications

References 49 publications

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells

A Role for Hepatic Leptin Signaling in Lipid Metabolism via Altered Very Low Density Lipoprotein Composition and Liver Lipase Activity in Mice

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Hepatic leptin signalling and subdiaphragmatic vagal efferents are not required for leptin-induced increases of plasma IGF binding protein-2 (IGFBP-2) in ob/ob mice

Abstract: Taken together, these data indicate that hepatic leptin signalling and subdiaphragmatic vagal inputs are not required for leptin upregulation of plasma IGFBP-2 nor blood glucose lowering in ob/ob mice.

Cited by 24 publications

References 49 publications

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

Leptin promotes K ATP channel trafficking by AMPK signaling in pancreatic β-cells

A Role for Hepatic Leptin Signaling in Lipid Metabolism via Altered Very Low Density Lipoprotein Composition and Liver Lipase Activity in Mice

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Leptin promotes K _ATP channel trafficking by AMPK signaling in pancreatic β-cells