High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons

Klöckener, Tim; Heß, Simon; Belgardt, Bengt F.; Paeger, Lars; Verhagen, L.A.W.; Husch, Andreas; Sohn, Jong Woo; Hampel, Brigitte; Dhillon, Harveen; Zigman, Jeffrey M.; Lowell, Bradford B.; Williams, Kevin W.; Elmquist, Joel K.; Horváth, Tamas L.; Kloppenburg, Peter; Brüning, Jens C.

doi:10.1038/nn.2847

Cited by 207 publications

(253 citation statements)

References 52 publications

(74 reference statements)

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“…23 In addition, we find ARL13B localization within the primary cilia of hypothalamic neurons, especially in the ventromedial nucleus of the hypothalamus, which is considered as a crucial site of regulation of energy homeostasis. [24][25][26][27] Finally, consistent with this finding, recent evidence in ciliopathies has linked obesity to the regulation of homeostasis within the hypothalamus. 28 Our zebrafish and MEF experiments indicate that the Y86C missense variant identified in this study is hypomorphic, as overexpression of Y86C cDNA is not efficient in rescuing the arl13b sco zebrafish and Arl13b hnn MEF phenotypes.…”

Section: Discussionsupporting

confidence: 76%

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

et al. 2014

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Joubert syndrome (JS) is a genetically heterogeneous autosomal recessive ciliopathy with 22 genes implicated to date, including a small, ciliary GTPase, ARL13B. ARL13B is required for cilia formation in vertebrates. JS patients display multiple symptoms characterized by ataxia due to the cerebellar vermis hypoplasia, and that can also include ocular abnormalities, renal cysts, liver fibrosis or polydactyly. These symptoms are shared with other ciliopathies, some of which display additional phenotypes, such as obesity. Here we identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient who displayed retinal defects and obesity. We demonstrate the variant disrupts ARL13B function, as its expression did not rescue the mutant phenotype either in Arl13b scorpion zebrafish or in Arl13b hennin mouse embryonic fibroblasts, while the wild-type ARL13B did. Finally, we show that ARL13B is localized within the primary cilia of neonatal mouse hypothalamic neurons consistent with the known link between hypothalamic ciliary function and obesity. Thus our data identify a novel ARL13B variant that causes JS and retinopathy and suggest an extension of the phenotypic spectrum of ARL13B mutations to obesity.

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Section: Discussionsupporting

confidence: 76%

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

et al. 2014

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“…For example, subsets of proopiomelanocortin (POMC) and steroidogenesis factor 1 (SF1) neurons are responsive to either leptin or insulin (15)(16)(17)(18)(19), and, therefore, it is not entirely known if the phenotype of mice with PI3K deletion in those neurons is due to lack of leptin or insulin signaling. Conditional deletion of PI3Kα or PI3Kβ in POMC and SF1…”

Section: Introductionmentioning

confidence: 99%

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

García-Galiano¹,

Borges²,

Donato³

et al. 2017

JCI Insight

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“…Among these neurons, several studies have shown that the steroidogenic factor 1 (SF1) expressing ones, which are restricted to the hypothalamic ventromedial nucleus (VMN), are important modulators of metabolic functions through their ability to detect variations of extracellular concentrations of glucose, insulin, leptin, and orexin to coordinate insulin/glucose homeostasis (1)(2)(3)(4)(5). The SF1 transcription factor itself is a key actor of energy homeostasis ,as SF1 knockout (KO) mice are obese (6).…”

mentioning

confidence: 99%

Hypothalamic ventromedial COUP-TFII protects against hypoglycemia-associated autonomic failure

Sabra-Makke

Maritan

Planchais

et al. 2013

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

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The nuclear receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) is an important coordinator of glucose homeostasis through its function in different organs such as the endocrine pancreas, adipose tissue, skeletal muscle, and liver. Recently we have demonstrated that COUP-TFII expression in the hypothalamus is restricted to a subpopulation of neurons expressing the steroidogenic factor 1 transcription factor, known to play a crucial role in glucose homeostasis. To understand the functional significance of COUP-TFII expression in the steroidogenic factor 1 neurons, we generated hypothalamic ventromedial nucleus-specific COUP-TFII KO mice using the cyclization recombination/locus of XoverP1 technology. The heterozygous mutant mice display insulin hypersensitivity and a leaner phenotype associated with increased energy expenditure and similar food intake. These mutant mice also present a defective counterregulation to hypoglycemia with altered glucagon secretion. Moreover, the mutant mice are more likely to develop hypoglycemia-associated autonomic failure in response to recurrent hypoglycemic or glucopenic events. Therefore, COUP-TFII expression levels in the ventromedial nucleus are keys in the ability to resist the onset of hypoglycemia-associated autonomic failure.H ypothalamic neurons are able to detect changes in the concentration of circulating hormones and nutrients and to relay this information into adaptive signals toward peripheral organs aimed at maintaining glucose homeostasis and energy balance. Among these neurons, several studies have shown that the steroidogenic factor 1 (SF1) expressing ones, which are restricted to the hypothalamic ventromedial nucleus (VMN), are important modulators of metabolic functions through their ability to detect variations of extracellular concentrations of glucose, insulin, leptin, and orexin to coordinate insulin/glucose homeostasis (1-5). The SF1 transcription factor itself is a key actor of energy homeostasis ,as SF1 knockout (KO) mice are obese (6). SF1 KO mice display an abnormal organization of the VMN, as SF1 is necessary for the terminal differentiation of the VMN neurons (7,8). SF1 itself directs a genetic program involved in energy homeostasis and leptin action in the VMN (9). Outside these functions, SF1 neurons are also part of the neurocircuitry involved in the counterregulatory response (CRR) to hypoglycemia. To prevent hypoglycemia, organisms have developed several survival mechanisms of CRR such as decreased insulin secretion and increased glucagon secretion to quickly reestablish euglycemia (10, 11). The decreased insulin secretion is a direct effect of hypoglycemia on the pancreatic β cells, while the other CRRs are mainly directed by the central nervous system and in part by the SF1 neurons (12)(13)(14). Overall the SF1 neuronal population is at the interface between sensing of glucose concentrations and modulation of insulin-dependent metabolism and energy homeostasis.Recently we have observed that Chicken Ovalbumin Upstre...

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High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons

Cited by 207 publications

References 52 publications

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

Hypothalamic ventromedial COUP-TFII protects against hypoglycemia-associated autonomic failure

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