Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight

Baskin, Denis G.; Lattemann, Dianne Figlewicz; Seeley, Randy J.; Woods, Stephen C.; Porte, Daniel; Schwartz, Michael W.

doi:10.1016/s0006-8993(99)01974-5

Cited by 346 publications

(239 citation statements)

References 120 publications

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“…In the CNS, the IR has distinct patterns of expression in the olfactory bulb, the hypothalamus and the pituitary [1,2,3], although its function in these regions is not completely understood. Previous studies have documented a role for insulin signalling in the regulation of food intake [4,5,6,7,8].…”

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confidence: 99%

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states. Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats. Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats. Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance. [Diabetologia (2003[Diabetologia ( ) 46:1629[Diabetologia ( -1640 Keywords Obesity, insulin resistance, hypothalamus, anorexia, signal transduction, phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism, mitogen-activated protein kinase. Abbreviations: ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor binding protein 2; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKC, Protein kinase C; Shc, Src-homology and collagen homology; SHP2, Src-homology phosphatase 2; TNF-α, Tumor-necrosis factor-α.

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Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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“…The regulation of energy intake is a complex, multifaceted process involving internal and external homeostatic and non-homeostatic signals. The homeostatic regulation of energy intake has gained considerable attention (see above) and involves key appetite hormones (e.g., acylated ghrelin, leptin) and their impact on energy intake [42,43]. However, non-homeostatic signals, such as learned behaviors, cognitive state, social context, external cues, and availability of food, also play a large role in the regulation of energy intake [44][45][46].…”

Section: Exercise and Neuronal Responsesmentioning

confidence: 99%

Exercise and Weight Loss: What Is the Evidence of Sex Differences?

Hagobian

Evero

2012

Curr Obes Rep

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Regular physical activity, in the form of structured daily exercise, plays a large role in obesity management. Previous studies suggest that when sedentary men and women start an exercise training program, men lose more body weight than women. This has led researchers to reason that women are better at defending weight than men in response to exercise. In this article, we review exercise studies examining weight loss in men and women, and highlight hormonal, neuronal, and ad libitum energy intake responses to physical activity that is consistent with or in disagreement with sex differences in weight loss. The developing story may impact our view on the use of physical activity to influence body weight and whether a true sex difference is evident.

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“…Neither is produced in the brain, and for each, there is a transport mechanism in the capillary endothelium that delivers the hormone to CNS receptors (157). Also like leptin, delivery of insulin to the brain, simulating energy surfeit and elevated adiposity, results in reduction of food intake (5,203). The contribution of brain insulin receptors to energy balance was recently highlighted by the finding that mice lacking brain insulin receptors are hyperphagic and obese (27).…”

Section: Insulinmentioning

confidence: 99%

The Neuroanatomical Axis for Control of Energy Balance

Grill

Kaplan

2002

Frontiers in Neuroendocrinology

351

219

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The hypothalamic feeding-center model, articulated in the 1950s, held that the hypothalamus contains the interoceptors sensitive to blood-borne correlates of available or stored fuels as well as the integrative substrates that process metabolic and visceral afferent signals and issue commands to brainstem mechanisms for the production of ingestive behavior. A number of findings reviewed here, however, indicate that sensory and integrative functions are distributed across a central control axis that includes critical substrates in the basal forebrain as well as in the caudal brainstem. First, the interoceptors relevant to energy balance are distributed more widely than had been previously thought, with a prominent brainstem complement of leptin and insulin receptors, glucose-sensing mechanisms, and neuropeptide mediators. The physiological relevance of this multiple representation is suggested by the demonstration that similar behavioral effects can be obtained independently by stimulation of respective forebrain and brainstem subpopulations of the same receptor types (e.g., leptin, CRH, and melanocortin). The classical hypothalamic model is also challenged by the integrative achievements of the chronically maintained, supracollicular decerebrate rat. Decerebrate and neurologically intact rats show similar discriminative responses to taste stimuli and are similarly sensitive to intake-inhibitory feedback from the gut. Thus, the caudal brainstem, in neural isolation from forebrain influence, is sufficient to mediate ingestive responses to a range of visceral afferent signals. The decerebrate rat, however, does not show a hyperphagic response to food deprivation, suggesting that interactions between forebrain and brainstem are necessary for the behavioral response to systemic/ metabolic correlates of deprivation in the neurologically intact rat. At the same time, however, there is evidence suggesting that hypothalamic-neuroendocrine responses to fasting depend on pathways ascending from brainstem. Results reviewed are consistent with a distributionist (as opposed to hierarchical) model for the control of energy balance that emphasizes: (i) control mechanisms endemic to hypothalamus and brainstem that drive their unique effector systems on the basis of local interoceptive, and in the brainstem case, visceral, afferent inputs and (ii) a set of uni-and bidirectional interactions that coordinate adaptive neuroendocrine, autonomic, and behavioral responses to changes in metabolic status. KEY WORDS: feeding behavior; leptin; glucose sensing; decerebrate; neuropeptide; hypothalamic model; caudal brainstem; energy balance.

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Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight

Cited by 346 publications

References 120 publications

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Exercise and Weight Loss: What Is the Evidence of Sex Differences?

The Neuroanatomical Axis for Control of Energy Balance

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