Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes

Lin, Xueying; Taguchi, Akiko; Park, Sunmin; Kushner, Jake A.; Fan, Li; Li, Yedan; White, Morris F.

doi:10.1172/jci22217

Cited by 275 publications

(149 citation statements)

References 66 publications

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“…In fact, hypothalamic ARC activity of Gsk3b has been shown to be increased in HF-fed and HF/high-fructose-fed mice (Benzler et al 2012, Anderson et al 2013, whereas overexpression in the mediobasal hypothalamus has been shown to lead to hyperphagia and obesity in mice that were challenged with an HF diet (Benzler et al 2012). The insulin receptor substrate 2 (IRS2) gene, another important modulator of insulin signalling, has been associated with severe human obesity (Lautier et al 2003), whereas the central ablation of Irs2 in mouse models has been shown to lead to obesity (Lin et al 2004, Sadagurski et al 2012. However, a recent study has shown an opposite phenotype, with obesity induced by an HF/high-fructose diet leading to an increase in Irs2 expression (Anderson et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Fam¹,

Sgambellone²,

Ruan³

et al. 2015

Journal of Endocrinology

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Obesity susceptibility in humans and in rodent strains varies in response to the consumption of high-energy density (HED) diets. However, the exact mechanism(s) involved in this susceptibility remain(s) unresolved. The aim of the present study was to gain greater insight into this susceptibility by using C57BL/6J (B6) mice that were separated into obesity-prone (diet-induced obese (DIO)) and obesity-resistant (diet-induced resistant (DR)) groups following an HED diet for 6 weeks. Physiological, biochemical and gene expression assessments of energy balance were performed in the DIO and DR mice on an HED diet and chow-fed mice. The increased weight gain of the DIO mice as compared to the DR mice was associated with increased energy intake and higher plasma leptin and adiponectin levels but not with reduced physical activity or resting energy expenditure. Hypothalamic Pomc gene expression was elevated, but there were no changes in Npy or Agrp expression. Adipose tissue leptin and adiponectin gene expression were significantly reduced in the DIO group as compared to the DR group. Interestingly, ileum expression of G protein-coupled receptor (Gpr) 40 (Gpr40) was significantly increased, whereas Gpr120, Gpr119, Gpr41, and glucagon-like peptide 1 (Glp1) were reduced. Contrastingly, the lower weight gain of the DR group was associated with elevated adipose tissue leptin and adiponectin gene expression, but there were no differences in plasma hormone or hypothalamic gene expression levels as compared to chow-fed mice. Therefore, the present data demonstrate that susceptibility and resistance to diet-induced weight gain in B6 mice appears to be predominantly driven by peripheral rather than hypothalamic modifications, and changes in gut-specific receptors are a potentially important contributor to this variation. Key Words" diet-induced obesity " high-energy density diet " body weight regulation

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Section: Discussionmentioning

confidence: 99%

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Fam¹,

Sgambellone²,

Ruan³

et al. 2015

Journal of Endocrinology

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“…It is now clear that defects in the action of insulin and leptin in the brain are implicated in the link between obesity and type 2 diabetes (Lin et al 2004;Obici et al 2002;Schwartz and Porte 2005). It is also important to point out that in human dysfunctions alterations in insulin and serotonin efficiency are closely related.…”

Section: Discussionmentioning

confidence: 99%

A Dietary Fat Excess Alters Metabolic and Neuroendocrine Responses Before the Onset of Metabolic Diseases

et al. 2008

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Early changes in neuroendocrine pathways are essential in the development of metabolic pathologies. Thus, it is important to have a better understanding of the signals involved in their initiation. Long-term consumption of high-fat diets induces insulin resistance, obesity, diabetes. Here, we have investigated early neural and endocrine events in the hypothalamus and hippocampus induced by a short-term high fat, low carbohydrate diet in adult male Wistar rats. The release of serotonin, which is closely associated with the actions of insulin and leptin, was measured, by electrochemical detection following reverse-phase liquid chromatography (HPLC), in the extracellular space of the medial hypothalamus and the dorsal hippocampus in samples obtained from non-anesthetized animals, by microdialysis. The high-fat diet had a specific effect on the hypothalamus. Serotonin release induced by food intake was reduced after 1 week, and effectively ceased after 6 weeks of the diet. After 1 week, there was an increased gene expression of the insulin receptor and the insulin receptor substrates IRS1 and IRS2, as measured by real-time PCR. After 6 weeks of diet, insulin gene expression increased. Leptinemia increased in all cases. This new data support the concept that high-fat diets, in addition to have peripheral effects, cause a rapid alteration in specific central mechanisms involved in energy and glucose homeostasis. The changes in the gene expression of insulin and signaling elements represent possible adaptations aimed at counterbalancing the reduced responsiveness of the serotonergic system to nutritional signals and maintaining homeostasis.

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“…Similar results were obtained in cortical tissue. Insulin signal transduction via the IR and IR substrate 2 has previously been shown to be involved in the regulation of appetite and body mass 35, 42. Concurrent measurements in brain activity, using electroencephalography (EEG), showed that enhanced cerebral insulin signalling with insulin detemir did indeed modulate cortical electrical activity (a significant increase in delta activity was reported).…”

Section: Central Nervous System Hypothesismentioning

confidence: 99%

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

Russell‐Jones

Danne

Hermansen

et al. 2015

Diabetes Obesity Metabolism

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Insulin therapy is often associated with adverse weight gain. This is attributable, at least in part, to changes in energy balance and insulin's anabolic effects. Adverse weight gain increases the risk of poor macrovascular outcomes in people with diabetes and should therefore be mitigated if possible. Clinical studies have shown that insulin detemir, a basal insulin analogue, exerts a unique weight‐sparing effect compared with other basal insulins. To understand this property, several hypotheses have been proposed. These explore the interplay of efferent and afferent signals between the muscles, brain, liver, renal and adipose tissues in response to insulin detemir and comparator basal insulins. The following models have been proposed: insulin detemir may reduce food intake through direct or indirect effects on the central nervous system (CNS); it may have favourable actions on hepatic glucose metabolism through a selective effect on the liver, or it may influence fluid homeostasis through renal effects. Studies have consistently shown that insulin detemir reduces energy intake, and moreover, it is clear that this shift in energy balance is not a consequence of reduced hypoglycaemia. CNS effects may be mediated by direct action, by indirect stimulation by peripheral mediators and/or via a more physiological counter‐regulatory response to insulin through restoration of the hepatic–peripheral insulin gradient. Although the precise mechanism remains unclear, it is likely that the weight‐sparing effect of insulin detemir can be explained by a combination of mechanisms. The evidence for each hypothesis is considered in this review.

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Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes

Cited by 275 publications

References 66 publications

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

A Dietary Fat Excess Alters Metabolic and Neuroendocrine Responses Before the Onset of Metabolic Diseases

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

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