SF-1 expression in the hypothalamus is required for beneficial metabolic effects of exercise

Fujikawa, Teppei; Castorena, Carlos M.; Pearson, Mackenzie; Kusminski, Christine M.; Ahmed, Newaz; Battiprolu, Pavan K.; Kim, Ki Woo; Lee, Syann; Hill, Joseph A.; Scherer, Philipp E.; Holland, William L.; Elmquist, Joel K.

doi:10.7554/elife.18206

Cited by 39 publications

(46 citation statements)

References 67 publications

(103 reference statements)

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“…This is consistent with studies showing that the VMH modulates fatty acid mobilisation and oxidation during exercise . Unexpectedly, deletion of SF‐1 in the VMH also impaired exercise‐induced increases in skeletal muscle mass and PGC‐1α mRNA expression …”

Section: The Vmh Regulates Metabolic Adaptations To Exercisesupporting

confidence: 91%

“…Optogenic or chemogenic activation of SF‐1 neurones alters SNS‐dependent physiological responses, such as increases in heart rate and glucose levels . We recently found that exercise training increases the mRNA levels of SF‐1 and putative SF‐1 target genes in the mediobasal hypothalamus (which includes the VMH) . Mice lacking SF‐1 from the VMH had a blunted response to training‐induced improvements in whole body energy expenditure, catecholamine release, fat loss and body composition.…”

Section: The Vmh Regulates Metabolic Adaptations To Exercisementioning

confidence: 99%

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The hypothalamic regulation of metabolic adaptations to exercise

Fujikawa

Castorena

Lee

et al. 2017

J Neuroendocrinology

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Our modern lifestyle is characterised by easy access to nutrient dense foods combined with limited physical activity. A sedentary lifestyle is one of several factors that have contributed to the global obesity epidemic and it also predisposes to chronic illnesses such as diabetes and cardiovascular disease. Although many studies have focused on the benefits of exercise in peripheral tissues, the contributions of the central nervous system to these exercise-induced metabolic adaptations are relatively unknown. The present review highlights the role of the ventromedial hypothalamus in regulating the metabolic response to exercise.

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Section: The Vmh Regulates Metabolic Adaptations To Exercisesupporting

confidence: 91%

Section: The Vmh Regulates Metabolic Adaptations To Exercisementioning

confidence: 99%

The hypothalamic regulation of metabolic adaptations to exercise

Fujikawa

Castorena

Lee

et al. 2017

J Neuroendocrinology

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“…Consistent with this notion, SF1 neurons in the VMH were shown to be necessary for the beneficial effects of exercise on metabolism. Deletion of SF1 in these neurons thus attenuated metabolic responses to exercise including the reduction in fat mass, improvement in glycemia, increase in energy expenditure, and induction of PGC1α expression in skeletal muscle 11) .…”

Section: Leptin Regulates Insulin Sensitivity In Skeletal Muscle Andmentioning

confidence: 99%

“…More recently, a single injection of FGF1 into the lateral ventricle was shown to induce a sustained reduction in blood glucose level associated with increased glucose uptake in skeletal muscle and the liver in several rodent models of type 2 diabetes 16) . SF1 neurons in the VMH have also been shown to be necessary for the beneficial effects of exercise on metabolism 11) . These and many other studies have thus revealed the important role of the hypothalamus in the control of glucose and lipid metabolism in skeletal muscle.…”

Section: The Cns Improves Glucose Metabolism In Insulin-deficient Andmentioning

confidence: 99%

“…We also showed that leptin stimulates fatty acid oxidation in skeletal muscle via activation of AMP-activated protein kinase (AMPK) both directly through interaction with the leptin receptor in skeletal muscle as well Correspondence: minokosh@nips.ac.jp as indirectly through activation of sympathetic nerves innervating the tissue 10) . SF1 neurons in the VMH were recently found to be required for the beneficial effects of exercise on metabolism including a reduction in fat mass, improvement in glycemia, increase in energy expenditure, and induction of the transcriptional coactivator PGC1α (peroxisome proliferator-activated receptor γ coactivator 1α) in muscle 11) . Furthermore, the orexin system is activated by a nonhomeostatic regulatory mechanism associated with taste stimulation and increases glucose metabolism in skeletal muscle during feeding via the VMH and sympathetic nerves innervating the tissue 12) .…”

Section: Introductionmentioning

confidence: 99%

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Hypothalamic control of glucose and lipid metabolism in skeletal muscle

Minokoshi

2017

JPFSM

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The hypothalamus controls glucose and lipid metabolism in peripheral tissues.Recent studies have revealed that the ventromedial hypothalamus (VMH) and arcuate nucleus (ARC) of the hypothalamus play an important role in the regulation of glucose and lipid metabolism in skeletal muscle and the liver. The fat-derived hormone leptin was thus shown to stimulate glucose uptake and fatty acid oxidation in red-type skeletal muscle by activating VMH neurons -likely mediated in part by augmentation of synaptic plasticity between leptin receptor and proopiomelanocortin (POMC)-expressing neurons in the ARC and melanocortin receptor (MCR)-expressing VMH neurons -and consequent activation of sympathetic nerves innervating the muscle tissue. The VMH -sympathetic nerve axis was also found to be activated by orexin-positive neurons in mediation of hedonic feeding-induced glucose uptake in redtype skeletal muscle. The effects of orexin and leptin on glucose metabolism in skeletal muscle are interconnected with those of insulin, with the action of VMH also being necessary for the beneficial effects of exercise on metabolism. Leptin ameliorates diabetic phenotypes in animals with uncontrolled insulin-deficient diabetes as well as in patients with or animal models of lipodystrophy through the central nervous system (CNS). Finally, a single injection of fibroblast growth factor 1 (FGF1) into the lateral ventricle was shown to induce sustained remission of hyperglycemia in several animal models of type 2 diabetes, at least in part by increasing glucose uptake in skeletal muscle. The CNS thus plays an important role in the control of glucose and lipid metabolism, with the VMH as well as POMC neurons being implicated as key regulators of such metabolism in skeletal muscle.

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ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis

Chhabra,

Bathina,

Faniyan

et al. 2023

Diabetologia

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Aims/hypothesis The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium−glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus. Methods Here we used a high molecular mass glucose–biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose–ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand–receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Results Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis. Conclusions/interpretation Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity. Graphical Abstract

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SF-1 expression in the hypothalamus is required for beneficial metabolic effects of exercise

Cited by 39 publications

References 67 publications

The hypothalamic regulation of metabolic adaptations to exercise

The hypothalamic regulation of metabolic adaptations to exercise

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis

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