Obesity is associated with hypothalamic injury in rodents and humans

Thaler, Joshua P.; Yi, Chun-Xia; Schur, Ellen A.; Guyenet, Stephan J.; Hwang, Bang H.; Dietrich, Marcelo O.; Zhao, Xiaolin; Sarruf, David A.; Izgur, Vitaly; Maravilla, Kenneth R.; Nguyen, Hong T.; Fischer, Jonathan; Matsen, Miles E.; Wisse, Brent E.; Morton, Gregory J.; Horváth, Tamas L.; Baskin, Denis G.; Tschöp, Matthias H.; Schwartz, Michael W.

doi:10.1172/jci59660

Cited by 1,566 publications

(2,117 citation statements)

References 44 publications

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“…If so, and if the cause of this impairment were understood in molecular and physiological terms, new opportunities for intervention might emerge. One possibility is that leptin resistance and obesity pathogenesis both arise from inflammation, gliosis, and injury of neurons in the arcuate nucleus, a possibility advanced in a recent JCI paper from our group (19). Our findings support a model in which "fixed structural change" affecting energy balance neurocircuits contributes to the defense of an elevated level of body fat mass in obese individuals, even after they adopt "healthy" diets and lifestyles that no longer perpetuate the CNS injury process.…”

supporting

confidence: 74%

Leptin and the brain: then and now

Schwartz

Baskin

2013

J. Clin. Invest.

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The discovery of the adipocyte hormone leptin and the demonstration that severe obesity in ob/ob and db/db mice results from mutation of genes encoding leptin and its receptor, respectively, ushered in a new era of obesity research. Our investigation into mechanisms mediating CNS actions of insulin led us to ask whether the two hormones act on a common set of hypothalamic targets. Our finding that this is indeed the case prompted studies that continue to this day. While substantial progress has been made in understanding brain mechanisms of leptin action, translating this knowledge into more effective treatment of obesity remains an elusive goal.

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supporting

confidence: 74%

Leptin and the brain: then and now

Schwartz

Baskin

2013

J. Clin. Invest.

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“…The present study does not claim it has exhausted the subject and future studies should be addressed in order to fully unveil the mechanism underlying the role of SAA in diet-induced obesity. Accordingly, the authors think the focus should be on intestinal permeability and also on neuronal control of energy homeostasis, as hypothalamic injury and the activation of inflammatory signalling are associated with obesity in both rodents and humans [47]. Duality of interest The authors declare that there is no duality of interest associated with this manuscript.…”

Section: Discussionmentioning

confidence: 99%

Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice

et al. 2016

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Aims/hypothesis Pre-adipocytes and adipocytes are responsive to the acute phase protein serum amyloid A (SAA). The combined effects triggered by SAA encompass an increase in preadipocyte proliferation, an induction of TNF-α and IL-6 release and a decrease in glucose uptake in mature adipocytes, strongly supporting a role for SAA in obesity and related comorbidities. This study addressed whether SAA depletion modulates weight gain and insulin resistance induced by a high-fat diet (HFD). Methods Male Swiss Webster mice were fed an HFD for 10 weeks under an SAA-targeted antisense oligonucleotide (ASO SAA ) treatment in order to evaluate the role of SAA in weight gain. Results With ASO SAA treatment, mice receiving an HFD did not differ in energy intake when compared with their controls, but were prevented from gaining weight and developing insulin resistance. The phenotype was characterised by a lack of adipose tissue expansion, with low accumulation of epididymal, retroperitoneal and subcutaneous fat content and decreased inflammatory markers, such as SAA3 and toll-like receptor (TLR)-4 expression, as well as macrophage infiltration into the adipose tissue. Furthermore, a metabolic status similar to chow-fed mice counterparts could be observed, with equivalent levels of leptin, adiponectin, IGF-I, SAA, fasting glucose and insulin, and remarkable improvement in glucose and insulin tolerance test profiles. Surprisingly, the expected HFD-induced metabolic endotoxaemia was also prevented by the ASO SAA treatment. Conclusions/interpretationThis study provides further evidence of the role of SAA in weight gain and insulin resistance. Moreover, we also suggest that beyond its proliferative and inflammatory effects, SAA is part of the lipopolysaccharide signalling pathway that links inflammation to obesity and insulin resistance.

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“…Taken together, these results indicate that SOCS3 expression increases in the AgRP neurons before POMC neurons and other hypothalamic cells during the course of high-fat feeding, suggesting that diet-induced SOCS3 up-regulation in the hypothalamus follows a distinct temporal and spatial pattern. In contrast to SOCS3, no significant increase of heat-shock protein 72 (HSP72), a marker for neuronal injury (22), or phosphorylation of eukaryotic initiation factor 2α (eIF2α), a marker for endoplasmic retictulum stress (23), was detected in AgRP neurons after 2-d high-fat feeding (Figs. S4 and S5).…”

Section: High-fat Diet-induced Up-regulation Of Socs3 Occurs In Agrpmentioning

confidence: 99%

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Olofsson

Unger

Cheung

et al. 2013

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

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Chronic consumption of a fat-rich diet leads to attenuation of leptin signaling in hypothalamic neurons, a hallmark feature of cellular leptin resistance. To date, little is known about the temporal and spatial dysregulation of neuronal function under conditions of nutrient excess. We show that agouti-related protein (AgRP)-expressing neurons precede proopiomelanocortin neurons in developing diet-induced cellular leptin resistance. High-fat diet-induced up-regulation of suppressor of cytokine signaling-3 (SOCS3) occurs in AgRP neurons before proopiomelanocortin and other hypothalamic neurons. SOCS3 expression in AgRP neurons increases after 2 d of high-fat feeding, but reduces after switching to a low-fat diet for 1 d. Consistently, transgenic overexpression of SOCS3 in AgRP neurons produces metabolic phenotypes resembling those observed after short-term high-fat feeding. We further show that AgRP neurons are the predominant cell type situated outside the blood-brain barrier in the mediobasal hypothalamus. AgRP neurons are more responsive to low levels of circulating leptin, but they are also more prone to development of leptin resistance in response to a small increase in blood leptin concentrations. Collectively, these results suggest that AgRP neurons are able to sense slight changes in plasma metabolic signals, allowing them to serve as first-line responders to fluctuation of energy intake. Furthermore, modulation of SOCS3 expression in AgRP neurons may play a dynamic and physiological role in metabolic fine tuning in response to short-term changes of nutritional status.M ost common forms of obesity, including diet-induced obesity, are associated with hyperleptinemia and impairment of leptin signaling in hypothalamic neurons, the hallmark feature of cellular leptin resistance. Suppressor of cytokine signaling-3 (SOCS3), a direct transcriptional product of STAT3, is up-regulated in the hypothalamus of diet-induced obese animals (1, 2). Mice with heterozygous mutation of the Socs3 gene, neuronal, or proopiomelanocortin (POMC)-specific deletion of the Socs3 gene are hypersensitive to leptin and resistant to diet-induced obesity (3-5). Conversely, up-regulation of SOCS3 in POMC neurons of chow-fed mice leads to increased body adiposity (6). In addition, wide-spread up-regulation of SOCS3 has been shown to be associated with neuronal inflammation in diet-induced obese animals (7). Thus SOCS3, which is up-regulated in chronic obesity, is commonly thought to play a pathophysiological role in obesity-associated leptin resistance.Multiple neuronal subtypes in several regions of the hypothalamus, including the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamic area, have been implicated in the regulation of energy balance and leptin action (8,9). A number of hypothalamic neurons and extrahypothalamic neurons express functional leptin receptor (10, 11). Among these neurons, POMC and agouti-related protein (AgRP) neurons are two key arcuate neuronal subtypes. POMC and AgRP neu...

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Obesity is associated with hypothalamic injury in rodents and humans

Cited by 1,566 publications

References 44 publications

Leptin and the brain: then and now

Leptin and the brain: then and now

Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

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