Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity

Zhang, Xiaoqing; Zhang, Guo; Zhang, Hai; Karin, Michael; Bai, Hua; Cai, Dongsheng

doi:10.1016/j.cell.2008.07.043

Cited by 1,239 publications

(1,455 citation statements)

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“…From these data, we conclude that changes in gut microbiota and changes in gut permeability could be signaled directly to the brain via the vagus nerve and that chronic exposure to low-level LPS could lead to the development of leptin resistance in VAN. It is unclear whether LPS could induce leptin resistance in the arcuate nucleus. There is evidence that proinflammatory signals in the hypothalamus result in impaired leptin signaling (35) and that NF-B signaling, an important downstream effector of LPS, induces SOCS-3 expression in the arcuate nucleus (37). Our data shed no light on the matter and suggest only that LPS levels are insufficient following 8 wk ingestion of a HF diet in Sprague-Dawley rats to effect leptin signaling in the arcuate nucleus.…”

Section: Discussioncontrasting

confidence: 47%

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Lartigue

Serre

Espero

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

152

142

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de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab 301: E187-E195, 2011. First published April 26, 2011; doi:10.1152/ajpendo.00056.2011.-Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.lipopolysaccharide; high-fat diet; suppressor of cytokine signaling-3 THE GUT PLAYS A CRUCIAL ROLE in sensing luminal contents that is important for the efficient digestion and absorption of ingested nutrients but also in integration of other physiological processes that regulate metabolism and energy expenditure, such as pancreatic ␤-cell function, hepatic function, and also food intake (34). In response to the presence or absence of food, enteroendocrine cells of the gut release anorexic or orexigenic hormones, respectively. The first site of integration of these signals occurs at the level of vagal afferent neurons (VAN), which project to and stimulate second-order neurons in the dorsal vagal complex of the hindbrain (27). VAN express receptors for many of the anorexigenic and orexigenic hormones released from the gut wall and mediate changes in gastrointestinal function and food intake in response to luminal nutrients (18).Leptin is a gut and adipose tissue-derived hormone that regulates a range of biological functions and processes, including energy intake and expenditure, body fat, neuroendocrine systems...

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Section: Discussioncontrasting

confidence: 47%

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Lartigue

Serre

Espero

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

152

142

View full text Add to dashboard Cite

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“…To elucidate the mechanism involved in the effect of ARA on central leptin resistance, we also It has been suggested that hypothalamic inflammation could be an important mediator of HFD-induced leptin resistance [11,38]. In the present study, the pro-inflammatory markers TNF-α, IL-1β, IL-6, and pIκBα were up-regulated at the hypothalamus by central ARA administration, suggesting that central ARA administration is sufficient to induce hypothalamic inflammation.…”

Section: Discussionsupporting

confidence: 53%

“…The JAK2-STAT3 pathway has been shown to mediate the effect of leptin on glucose metabolism [8], and the PI3K-Akt pathway is involved in both glucose [9] and lipid metabolism [10]. Recent studies have provided strong evidence for the contribution of hypothalamic inflammation to HFD-induced leptin resistance and/or type 2 diabetes mellitus [11,12].…”

mentioning

confidence: 99%

Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice

Cheng

Zhang

et al. 2015

Molecular and Cellular Endocrinology

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X. (2015). Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice. Molecular and Cellular Endocrinology, Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice AbstractEpidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids (PUFA) is associated with the development of leptin resistance and obesity. We aim to examine the central effect of n-6 PUFA, arachidonic acid (ARA) on leptin sensitivity and leptin-regulated hepatic glucose and lipid metabolism. We found that intracerebroventricular injection of ARA (25 nmol/day) for 2.5 days reversed the effect of central leptin on hypothalamic JAK2, pSTAT3, pAkt, and pFOXO1 protein levels, which was concomitant with a pro-inflammatory response in the hypothalamus. ARA also attenuated the effect of central leptin on hepatic glucose and lipid metabolism by reversing the mRNA expression of the genes involved in gluconeogenesis (G6Pase, PEPCK), glucose transportation (GLUT2), lipogenesis (FAS, SCD1), and cholesterol synthesis (HMG-CoA reductase). These results indicate that an increased exposure to central n-6 PUFA induces central cellular leptin resistance with concomitant defective JAK2-STAT3 and PI3K-Akt signaling. Disciplines Medicine and Health Sciences 2 AbstractEpidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids

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“…We have previously shown that SOCS3 expression is Cre-dependent, and its expression is upregulated approximately twofold in Cre-expressing cells upon recombination (6). The Tg.Agrp-Cre mice have been used and validated in a number of independent studies (7,(25)(26)(27)(28)(29)(30)(31). The resultant mutant mice, termed AgRP-SOCS3-OE, were born in Mendelian ratio with no detectable gross abnormalities.…”

Section: Expression Of Socs3 In Agrp Neurons Is Dynamically Modulated Inmentioning

confidence: 99%

“…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.…”

mentioning

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.

122

111

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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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Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity

Cited by 1,239 publications

References 38 publications

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice

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

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