Leptin activates ATP‐sensitive potassium channels in the rat insulin‐secreting cell line, CRI‐G1

Harvey, Jenni; McKenna, Fiona-Mairéad; Herson, Paco S.; Spanswick, David; Ashford, M. L. J.

doi:10.1111/j.1469-7793.1997.527bd.x

Cited by 95 publications

(100 citation statements)

References 26 publications

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“…As would be expected, leptin blocked insulin secretion by islets from ob/ob mice but not by db/db mice which lack the leptin receptor [65]. These effects may be mediated by the ATP-sensitive potassium channel [66,67].…”

Section: Regulation Of Leptin By Insulinmentioning

confidence: 58%

Nutritional regulation of leptin in humans

Coleman

Herrmann

1999

Diabetologia

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OverviewPositional cloning of the defective gene in genetically obese ob/ob mice identified leptin as the long-sought hormone that communicates information about adipocyte metabolism to the brain [1]. Supplying leptin to genetically deficient ob/ob mice increases metabolic rate, body temperature and general activity and decreases food intake, body weight and adiposity [1±4]. Additionally, the importance of leptin to reproduction has been highlighted by the lack of sexual maturation in people who are genetically deficient in leptin [5] or the leptin receptor [6]. Although many of leptin's effects are centrally mediated, there is growing evidence that peripheral leptin receptors mediate leptin's proliferative effects on haemopoietic cells [7] and its anti-lipogenic effects on muscle and pancreatic islets [8,9].Because leptin has a critical role in regulating energy metabolism, adipose stores and body weight, questions have been raised concerning the control of leptin synthesis and secretion and the function of leptin in controlling satiety and food intake. Basal or fasting leptin values are higher in women than men, increase during the course of pregnancy and, in both healthy adults and those with Type II (non-insulindependent) diabetes mellitus, are strongly correlated with per cent body fat or BMI [10,11] and adipose tissue mass [12±15]. Despite these strong correlations, people with similar degrees of adiposity have circulating leptin concentrations that vary considerably. Thus, factors other than adipocyte size and fat content must influence leptin production. Further, the regulation of leptin's diurnal pattern of secretion is still to be explained.In this review we summarize current data, primarily from human studies, that address the nutritional controls on leptin synthesis and secretion and point out fruitful areas for future study. Excellent recent reviews should be consulted for information on the leptin receptor, other aspects of leptin's effects, and the relation of leptin to other hormones that regulate food intake and energy expenditure [16±22]. Leptin regulation by fasting, refeeding and overfeedingFasting and refeeding. During short-term energy restriction, plasma leptin concentrations decrease much more than the amount of weight or adipose tissue lost. For example, lean and obese adults who fasted for 52 to 96 h lost less than 4 % of body weight but the leptin concentrations decreased 54 to 72 % [23±25]. In careful long-term studies of lean and obese people who were either losing weight or maintaining a defined weight loss, leptin concentrations were lower during the period of loss than the period of weight maintenance at the same body composition [26]. After a 4 day fast followed by an additional 6 days of fasting during which an intravenous infusion of 5 % glucose was given, leptin increased 80 % within the first 24 h, even though glucose provided only 338 kcal/day [25]. Although it is possible that the previous 4 day fast confounded these results [27], taken together, these studies suggest that ...

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Section: Regulation Of Leptin By Insulinmentioning

confidence: 58%

Nutritional regulation of leptin in humans

Coleman

Herrmann

1999

Diabetologia

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“…Voltage clamp analysis (Fig. 4A) showed that leptin increased the mean cell slope conductance from 0.73 Ϯ 0.11 to 1.62 Ϯ 0.22 nanosiemens (n ϭ 19; p Ͻ 0.05), an action reduced by tolbutamide to 0.42 Ϯ 0.04 nanosiemens (n ϭ 14; p Ͻ 0.05), indicating that the increase in current responsible for the augmented slope conductance and ␤-cell hyperpolarization by leptin is due to K ATP channel opening (14,15,30). The presence of DMAT (10 M) in the electrode solution (and, therefore, cell interior) resulted in a mean resting membrane potential of Ϫ44.8 Ϯ 3.4 mV (p Ͼ 0.05 compared with control).…”

Section: Resultsmentioning

confidence: 99%

Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Ning

Miller

Laidlaw

et al. 2009

Journal of Biological Chemistry

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Leptin activates multiple signaling pathways in cells, including the phosphatidylinositol 3-kinase pathway, indicating a degree of cross-talk with insulin signaling. The exact mechanisms by which leptin alters this signaling pathway and how it relates to functional outputs are unclear at present. A previous study has established that leptin inhibits the activity of the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), an important tumor suppressor and modifier of phosphoinositide signaling. In this study we demonstrate that leptin phosphorylates multiple sites on the C-terminal tail of PTEN in hypothalamic and pancreatic ␤-cells, an action not replicated by insulin. Inhibitors of the protein kinases CK2 and glycogen synthase kinase 3 (GSK3) block leptin-mediated PTEN phosphorylation. PTEN phosphorylation mutants reveal the critical role these sites play in transmission of the leptin signal to F-actin depolymerization. CK2 and GSK3 inhibitors also prevent leptinmediated F-actin depolymerization and consequent ATP-sensitive K ؉ channel opening. GSK3 kinase activity is inhibited by insulin but not leptin in hypothalamic cells. Both hormones increase N-terminal GSK3 serine phosphorylation, but in hypothalamic cells this action of leptin is transient. Leptin, not insulin, increases GSK3 tyrosine phosphorylation in both cell types. These results demonstrate a significant role for PTEN in leptin signal transmission and identify GSK3 as a potential important signaling node contributing to divergent outputs for these hormones.Efficient signaling by leptin and insulin is essential for the maintenance of body energy homeostasis, with disruptions in these processes strongly associated with diabetes and obesity (1, 2) and, at least for insulin, neurodegenerative disorders such as Alzheimer disease (3, 4). In recent years there has been a significant increase in understanding the intracellular signaling processes associated with the actions of insulin on a wide variety of cell types (5). However, our knowledge of leptin signaling is less advanced, with most studies indicating that leptin and insulin share many signaling intermediates in common, often leading to similar cellular outcomes (6, 7). In particular, signaling through the STAT (signal transducers and activators of transcription), mitogen-activated protein kinase, and PI3K 3 pathways have been reported extensively in numerous cell types for both leptin and insulin (5, 8).Nevertheless, leptin and insulin can cause differing and sometimes opposing cellular outputs, even on the same cell type. This is demonstrated in hypothalamic neurons, where electrophysiological or imaging studies show differential outcomes for leptin and insulin action (9 -11). Thus, although superficially leptin may utilize the same signaling pathways as insulin, the exact nature of the leptin-induced signaling intermediates and their interplay with one another and with individual effectors is still relatively unknown. Recently, it was demonstrated that although leptin, lik...

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“…The proposed mechanism seems to affect the phospholipase C (PLC)/protein kinase C (PKC)-mediated pathway regulating insulin secretion. Modulation by leptin of several steps in this pathway were described: lowering of intracellular Ca 2+ concentration and activation of ATP-sensitive K + channels (166,169,173); a speci®c inhibition of PLC-mediated insulin secretion, which is enhanced in ob/ob mice (167,174); and reduction of PKC, a Ca 2+ -dependent mediator in the second phase of the PLC signal pathway (167,170). The insulinsuppressive effect of leptin could also partly be mediated by activation of phosphodiesterase 3B (171,175), leading to suppression of cAMP levels and inhibition of GLP-1-stimulated insulin secretion.…”

Section: Effect Of Leptin On Insulin Secretionmentioning

confidence: 99%

Human leptin: from an adipocyte hormone to an endocrine mediator

2000

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Leptin is a mainly adipocyte-secreted protein that was discovered 5 years ago. Most of the research following this discovery focused on the role of leptin in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more and more data are emerging that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function as a metabolic and neuroendocrine hormone. It is now clear that it is especially involved in glucose metabolism, as well as in normal sexual maturation and reproduction. Besides this, interactions with the hypothalamic±pituitary±adrenal, thyroid and GH axes and even with haematopoiesis and the immune system have also been described. It has been shown that leptin secretion by the adipocyte is partly regulated by other hormones, such as insulin, cortisol, and sex steroids, mainly testosterone. Also, other hormones like thyroid hormone and GH are possibly involved in leptin synthesis. Leptin itself exerts effects on different endocrine axes, mainly on the hypothalamic±pituitary±gonadal axis and on insulin metabolism, but also on the hypothalamic±pituitary±adrenal, thyroid and GH axes.Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation.

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Leptin activates ATP‐sensitive potassium channels in the rat insulin‐secreting cell line, CRI‐G1

Cited by 95 publications

References 26 publications

Nutritional regulation of leptin in humans

Nutritional regulation of leptin in humans

Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Human leptin: from an adipocyte hormone to an endocrine mediator

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