Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity

Guo, Tingqing; Mármol, Patricia; Moliner, Annalena; Björnholm, Marie; Zhang, Chao; Shokat, Kevan M.; Ibáñez, Carlos F.

doi:10.7554/elife.03245

Cited by 71 publications

(110 citation statements)

References 43 publications

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“…ACVR1Cdeficient mice have been reported to have reduced body fat when fed a high-fat diet (37,39) and have improved glucose tolerance and insulin sensitivity when obese (37). Chemical inhibition of ACVR1C has also been shown to reduce fat accumulation and increase lipolysis in mice (40). Rats with streptozocin-induced diabetes show elevated ALK7 expression, and shRNA knockdown of ACVR1C reduces arterial stiffness in this model (41).…”

Section: Discussionmentioning

confidence: 85%

DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

et al. 2018

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A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic b-cells), which independently associated with reduced WHRadjBMI: Asn150His (20.09 SD, P = 3.4 3 10 217 ), Ile195Thr (20.15 SD, P = 1.0 3 10 29 ), Ile482Val (20.019 SD, P = 1.6 3 10 25 ), and rs72927479 (20.035 SD, P = 2.6 3 10 212 ). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 3 10 213 ). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.

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Section: Discussionmentioning

confidence: 85%

DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

et al. 2018

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“…), and β‐adrenoreceptor‐mediated lipolysis and lipid oxidation in adipose tissue are severely impaired in obesity (Guo et al . ). Decreased responsiveness to the sympathetic nervous system could be caused by polymorphisms in genes that are involved in catecholamine signal transduction and have effects on fat cell lipolysis (Arner, ).…”

Section: Epidemiology Of Metabolic Diseasesmentioning

confidence: 97%

“…Data in the literature also agree that insulin resistance states are characterized by sympathetic predominance in a resting/basal state and reduced sympathetic responsiveness after physiological sympathetic stimuli. In fact, sympathetic nervous system responses to carbohydrate ingestion are blunted in insulin-resistant states , and β-adrenoreceptormediated lipolysis and lipid oxidation in adipose tissue are severely impaired in obesity (Guo et al 2014). Decreased responsiveness to the sympathetic nervous system could be caused by polymorphisms in genes that are involved in catecholamine signal transduction and have effects on fat cell lipolysis (Arner, 2001).…”

Section: Sympathetic Nervous System Contribution To Metabolic Diseasesmentioning

confidence: 99%

Insulin resistance: a new consequence of altered carotid body chemoreflex?

Conde

Ribeiro

Melo

et al. 2016

The Journal of Physiology

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Reactive oxygen species Inflammation HyperinsulinaemiaHypercaloric diets, obesity Carotid body overactivation Insulin resistance HypertensionSympathetic nervous system activity ? Abstract Metabolic diseases affect millions of individuals across the world and represent a group of chronic diseases of very high prevalence and relatively low therapeutic success, making them suitable candidates for pathophysiological studies. The sympathetic nervous system (SNS) contributes to the regulation of energy balance and energy expenditure both in physiological and pathological states. For instance, drugs that stimulate sympathetic activity decrease food intake, increase resting metabolic rate and increase the thermogenic response to food, while Silvia Conde's research focuses on understanding the physiology of the autonomic nervous system, in particular the carotid body, and in the application of its findings to pathological states allowing the identification of molecular targets for therapy. pharmacological blockade of the SNS has opposite effects. Likewise, dysmetabolic features such as insulin resistance, dyslipidaemia and obesity are characterized by a basal overactivation of the SNS. Recently, a new line of research linking the SNS to metabolic diseases has emerged with the report that the carotid bodies (CBs) are involved in the development of insulin resistance. The CBs are arterial chemoreceptors that classically sense changes in arterial blood O 2 , CO 2 and pH levels and whose activity is known to be increased in rodent models of insulin resistance. We have shown that selective bilateral resection of the nerve of the CB, the carotid sinus nerve (CSN), totally prevents diet-induced insulin resistance, hyperglycaemia, dyslipidaemia, hypertension and sympathoadrenal overactivity. These results imply that the beneficial effects of CSN resection on insulin action and glucoregulation are modulated by target-related efferent sympathetic nerves through a reflex that is initiated in the CBs. It also highlights modulation of CB activity as a putative future therapeutic intervention for metabolic diseases. Abstract figure legend Role of the carotid body (CB) in the development of insulin resistance through an increase in sympathetic nervous system activity. Obesity and hypercaloric diets promote hyperinsulinaemia, inflammation and the increase in oxidative stress. The hyperinsulinaemia and/or inflammation and/or reactive oxygen species stimulate the CB and promote its overactivation that contributes to the excessive sympatho-excitation that originates insulin resistance and hypertension.Abbreviations CB, carotid body; CSN, carotid sinus nerve; NEFAs, non-esterified fatty acids; OSA, obstructive sleep apnoea; SNS, sympathetic nervous system.

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“…3b), we next investigated the mechanism of Nlrp3 inflammasome-induced impaired lipolysis. GDF3, a TGFβ family member, is secreted by macrophages and ligates multiple receptors, including nodal or activin-like kinase-7 (ALK7) on adipocytes to inhibit catecholamine-induced lipolysis 23,24 . In agreement, VAT from Gdf3 −/− mice show increased glycerol release (Fig.…”

Section: Main Textmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

369

352

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Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

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Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity

Cited by 71 publications

References 43 publications

DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

Insulin resistance: a new consequence of altered carotid body chemoreflex?

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

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