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• W2002138834 abstract "Leptin mimics many of the antidiabetic actions of insulin in insulin-deficient diabetes, but the mechanism is controversial. Fujikawa et al., 2013Fujikawa T. Berglund E.D. Patel V.R. Giorgio Ramadori G. Vianna C.R. Vong L. Thorel F. Chera S. Herrera P.L. Lowell B.B. et al.Cell Metab. 2013; 18 (this issue): 431-444Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar reveal that leptin receptors in γ-aminobutyric acid (GABA)-ergic and pro-opiomelanocortin (POMC) neurons in the central nervous system are sufficient to mediate the lifesaving and antidiabetic actions of leptin in insulin-deficient mice. Leptin mimics many of the antidiabetic actions of insulin in insulin-deficient diabetes, but the mechanism is controversial. Fujikawa et al., 2013Fujikawa T. Berglund E.D. Patel V.R. Giorgio Ramadori G. Vianna C.R. Vong L. Thorel F. Chera S. Herrera P.L. Lowell B.B. et al.Cell Metab. 2013; 18 (this issue): 431-444Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar reveal that leptin receptors in γ-aminobutyric acid (GABA)-ergic and pro-opiomelanocortin (POMC) neurons in the central nervous system are sufficient to mediate the lifesaving and antidiabetic actions of leptin in insulin-deficient mice. The discovery of insulin in 1921–1922 and its profound, lifesaving effect on people with type 1 diabetes (T1DM) was one of the miracles of modern medicine. Normal glucose control without insulin seemed impossible. Yet, recent studies demonstrate that the adipocyte-secreted, anorexigenic hormone, leptin, also has potent antidiabetic actions in insulin-deficient diabetes. In this issue, Fujikawa et al. elucidate the underlying mechanisms by identifying specific neuronal subtypes that can mediate the glucose-lowering effects of leptin in the absence of insulin (Fujikawa et al., 2013Fujikawa T. Berglund E.D. Patel V.R. Giorgio Ramadori G. Vianna C.R. Vong L. Thorel F. Chera S. Herrera P.L. Lowell B.B. et al.Cell Metab. 2013; 18 (this issue): 431-444Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Although insulin therapy is effective for T1DM, diabetic complications including retinopathy, nephropathy, cardiovascular disease, and lower hindlimb amputation are still major problems. Insulin therapy lacks the precision necessary to mimic the finely tuned dynamics of insulin secretion from pancreatic β cells. Intensive insulin treatment reduces the incidence and progression of diabetic complications but increases the frequency of severe hypoglycemia and may contribute to increased adiposity, hepatic steatosis, and adverse plasma lipoprotein profiles in T1DM. Leptin could be a potential adjunctive therapy for T1DM because of its beneficial effects on glucose metabolism and its antisteatotic and appetite-suppressive effects (Wang et al., 2010Wang M.Y. Chen L. Clark G.O. Lee Y. Stevens R.D. Ilkayeva O.R. Wenner B.R. Bain J.R. Charron M.J. Newgard C.B. Unger R.H. Proc. Natl. Acad. Sci. USA. 2010; 107: 4813-4819Crossref PubMed Scopus (250) Google Scholar, Morton and Schwartz, 2011Morton G.J. Schwartz M.W. Physiol. Rev. 2011; 91: 389-411Crossref PubMed Scopus (234) Google Scholar). Leptin increases glucose utilization in peripheral tissues, suppresses hepatic glucose production, and reverses hyperglucagonemia in insulin-deficient rodents (German et al., 2011German J.P. Thaler J.P. Wisse B.E. Oh-I S. Sarruf D.A. Matsen M.E. Fischer J.D. Taborsky Jr., G.J. Schwartz M.W. Morton G.J. Endocrinology. 2011; 152: 394-404Crossref PubMed Scopus (121) Google Scholar, Wang et al., 2010Wang M.Y. Chen L. Clark G.O. Lee Y. Stevens R.D. Ilkayeva O.R. Wenner B.R. Bain J.R. Charron M.J. Newgard C.B. Unger R.H. Proc. Natl. Acad. Sci. USA. 2010; 107: 4813-4819Crossref PubMed Scopus (250) Google Scholar) (Figure 1). These effects are independent of leptin’s anorexic effect and appear to be mediated through the hypothalamus, although the neuronal circuits are unknown. Fujikawa et al. used two complementary models of insulin-deficient diabetes induced by (1) the pancreatic β cell toxin streptozotocin or (2) diphtheria toxin treatment in mice expressing the diphtheria-toxin receptor driven by a rat insulin promoter (RIP), which ablated nearly all pancreatic β cells. To determine which neuronal population(s) mediate the effects of intracerebroventricular (i.c.v.) leptin—leptin administered directly into the brain ventricles—in insulin-deficient mice, the authors deleted or re-expressed the leptin receptor (LEPR) in a neuron type-specific manner. LEPR ablation selectively in POMC neurons marginally blunted the hyperglycemia-lowering action of i.c.v. leptin in insulin-deficient mice, and LEPR ablation in steroidogenic factor 1 (SF1) neurons (enriched in the ventromedial hypothalamus, VMH) had no effect. Furthermore, LEPR re-expression in POMC neurons alone in insulin-deficient mice lacking LEPR in all other tissues failed to improve hyperglycemia or survival in response to i.c.v. leptin. In contrast, LEPR re-expression selectively in GABAergic neurons increased survival of insulin-deficient mice treated with i.c.v. leptin, partially improved hyperglycemia, and fully reversed hyperglucagonemia. LEPR re-expression in both GABAergic and POMC neurons had additive metabolic effects and was sufficient to mediate the lifesaving and antidiabetic effects of leptin in insulin-deficient mice. The major input was from GABAergic neurons. Fujikawa et al.’s paper raises important questions. First, which GABAergic neurons mediate the antidiabetic effects of leptin, and what are the target neurons? GABAergic neurons expressing LEPRs are present in the arcuate, dorsomedial hypothalamus, and lateral hypothalamus. Although leptin injection into VMH can normalize diabetic hyperglycemia, LEPR in SF1-expressing neurons is not necessary for these effects (Meek et al., 2013Meek T.H. Matsen M.E. Dorfman M.D. Guyenet S.J. Damian V. Nguyen H.T. Taborsky Jr., G.J. Morton G.J. Endocrinology. 2013; PubMed Google Scholar, Fujikawa et al., 2013Fujikawa T. Berglund E.D. Patel V.R. Giorgio Ramadori G. Vianna C.R. Vong L. Thorel F. Chera S. Herrera P.L. Lowell B.B. et al.Cell Metab. 2013; 18 (this issue): 431-444Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Leptin may act on presynaptic GABAergic neurons projecting to the VMH or other regions. In the arcuate, neuropeptide Y (NPY) and agouti-related peptide (AgRP)-expressing neurons corelease GABA, which potently inhibits POMC neuronal activity. Leptin suppresses the neuronal activity of NPY/AgRP/GABAergic neurons, thereby activating POMC neurons (Morton and Schwartz, 2011Morton G.J. Schwartz M.W. Physiol. Rev. 2011; 91: 389-411Crossref PubMed Scopus (234) Google Scholar). Loss of GABAergic signaling in a subset of arcuate AgRP/NPY/GABAergic neurons that project to the parabrachial nucleus leads to starvation (Wu et al., 2009Wu Q. Boyle M.P. Palmiter R.D. Cell. 2009; 137: 1225-1234Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). Furthermore, mice lacking GABA release in arcuate RIP-expressing neurons have decreased energy expenditure and become obese via a circuit involving paraventricular hypothalamic neurons (Kong et al., 2012Kong D. Tong Q. Ye C. Koda S. Fuller P.M. Krashes M.J. Vong L. Ray R.S. Olson D.P. Lowell B.B. Cell. 2012; 151: 645-657Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar), underscoring the importance of hypothalamic GABAergic neurons in energy balance. Second, what are the mechanism(s) for leptin’s actions in peripheral tissues (Figure 1), and is suppression of hyperglucagonemia critical? Glucagon appears to be essential for development of hyperglycemia in insulin-deficient mice (Wang et al., 2010Wang M.Y. Chen L. Clark G.O. Lee Y. Stevens R.D. Ilkayeva O.R. Wenner B.R. Bain J.R. Charron M.J. Newgard C.B. Unger R.H. Proc. Natl. Acad. Sci. USA. 2010; 107: 4813-4819Crossref PubMed Scopus (250) Google Scholar). But the antidiabetic actions of i.c.v. leptin are partial in diabetic mice in which LEPR is re-expressed in GABAergic neurons alone, while hyperglucagonemia is fully reversed. Thus, suppression of hyperglucagonemia is not sufficient for the full antidiabetic actions of leptin. Furthermore, suppression of hyperglucagonemia does not explain the leptin-induced glucose uptake in peripheral tissues. β-adrenergic receptors mediate leptin-stimulated glucose uptake in brown fat and muscle in lean, nondiabetic rodents (Minokoshi et al., 1999Minokoshi Y. Haque M.S. Shimazu T. Diabetes. 1999; 48: 287-291Crossref PubMed Scopus (231) Google Scholar). But Fujikawa et al. showed that the antidiabetic actions of i.c.v. leptin were intact in β1,β2,β3-adrenergic receptor-knockout mice, indicating that different pathways are engaged by hypothalamic neurons to regulate glucose homeostasis in the presence and absence of insulin. Insulin-like growth factor binding protein 2 is induced in liver by leptin (Hedbacker et al., 2010Hedbacker K. Birsoy K. Wysocki R.W. Asilmaz E. Ahima R.S. Farooqi I.S. Friedman J.M. Cell Metab. 2010; 11: 11-22Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), and overexpression improves hyperglycemia in insulin-deficient mice. Whether it mediates the antidiabetic effects of i.c.v. leptin is unknown. Third, how do the CNS effects of leptin on glucose homeostasis integrate with the peripheral and CNS effects of insulin? Insulin inhibits hepatic glucose production both directly and through the hypothalamus (Figure 1) (Pocai et al., 2005Pocai A. Lam T.K. Gutierrez-Juarez R. Obici S. Schwartz G.J. Bryan J. Aguilar-Bryan L. Rossetti L. Nature. 2005; 434: 1026-1031Crossref PubMed Scopus (519) Google Scholar). The relative importance of these CNS effects of insulin in normal physiology and whether impairment of these effects contributes to metabolic abnormalities in T1DM is unknown. Furthermore, whether CNS insulin acts through the same GABAergic neurons as leptin is unknown. The most fundamental question is whether leptin therapy will be effective in T1DM people. Independent of leptin’s insulin-mimicking effects, its potential appetite-suppressing effects could be beneficial for glucose control in T1DM. T1DM rodents are leptin deficient due to reduced fat mass resulting from uncontrolled diabetes, while T1DM people who are controlled with insulin therapy have normal or increased fat mass. Thus, leptin supplementation in leptin-sufficient T1DM humans may not have the same glycemic effects as leptin replacement in leptin-deficient T1DM mice. Furthermore, potential adverse effects of leptin such as hypertension and proinflammatory and procoagulatory effects may occur when leptin levels are raised above normal in T1DM humans. If used in combination with insulin, leptin’s effect to potently suppress glucagon may increase the risk for severe hypoglycemia in T1DM people. Increased GABAergic output in VMH contributes to impaired counterregulatory responses to hypoglycemia in diabetes. Collectively, recent studies provide convincing evidence that leptin has beneficial effects on glucose homeostasis in insulin-deficient (and leptin-deficient) mice via the CNS. Fujikawa et al. found that the vast majority of leptin’s antidiabetic effects may be mediated by CNS GABAergic neurons. While further studies are needed to determine the full neuronal circuitry, these findings extend our understanding of CNS control of glucose metabolism. Clinical studies are needed to determine whether leptin or molecules targeting the GABAergic pathways mediating leptin’s glucose-lowering effects could be effective and safe adjunctive therapies for T1DM and whether, by lowering the insulin dose, these could diminish some adverse effects of intensive insulin therapy without increasing the risk of hypoglycemia. Leptin Engages a Hypothalamic Neurocircuitry to Permit Survival in the Absence of InsulinFujikawa et al.Cell MetabolismSeptember 03, 2013In BriefThe dogma that life without insulin is incompatible has recently been challenged by results showing the viability of insulin-deficient rodents undergoing leptin monotherapy. Yet, the mechanisms underlying these actions of leptin are unknown. Here, the metabolic outcomes of intracerebroventricular (i.c.v.) administration of leptin in mice devoid of insulin and lacking or re-expressing leptin receptors (LEPRs) only in selected neuronal groups were assessed. Our results demonstrate that concomitant re-expression of LEPRs only in hypothalamic γ-aminobutyric acid (GABA) and pro-opiomelanocortin (POMC) neurons is sufficient to fully mediate the lifesaving and antidiabetic actions of leptin in insulin deficiency. Full-Text PDF Open Archive" @default.
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• W2002138834 title "Leptin, GABA, and Glucose Control" @default.
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