New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes

Despite the substantial role played by the hypothalamus in the regulation of energy balance and glucose homeostasis, the exact mechanisms and neuronal circuits underlying this regulation remain poorly understood. In the last 15 years, investigations using transgenic models, optogenetic, and chemogenetic approaches have revealed that SF1 neurons in the ventromedial hypothalamus are a specific lead in the brain’s ability to sense glucose levels and conduct insulin and leptin signaling in energy expenditure and glucose homeostasis, with minor feeding control. Deletion of hormonal receptors, nutritional sensors, or synaptic receptors in SF1 neurons triggers metabolic alterations mostly appreciated under high-fat feeding, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. Although these studies have provided exciting insight into the implications of hypothalamic SF1 neurons on whole-body energy homeostasis, new questions have arisen from these results. Particularly, the existence of neuronal sub-populations of SF1 neurons and the intricate neurocircuitry linking these neurons with other nuclei and with the periphery. In this review, we address the most relevant studies carried out in SF1 neurons to date, to provide a global view of the central role played by these neurons in the pathogenesis of obesity and diabetes.

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Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90932.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. E1101-E1109 ◽

Cited By ~ 37

Author(s):

Victoria E. Cotero ◽

Vanessa H. Routh

Keyword(s):

Energy Homeostasis ◽

Ventromedial Hypothalamus ◽

Glucose Sensing ◽

Hypothalamic Nucleus ◽

Compensatory Mechanisms ◽

Glucose Levels ◽

Compound C ◽

Obesity And Diabetes ◽

Extracellular Glucose ◽

Pi3k Signaling Pathway

Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose-sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose-sensing neurons. Glucose-sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Our results indicate that insulin opens the KATP channel on VMH GE neurons in 5, 2.5, and 0.1 mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1 mM. This change in the glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (10 nM) but not by the mitogen-activated kinase (MAPK) inhibitor PD-98059 (PD; 50 μM). Finally, neither the AMPK inhibitor compound C nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered.

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Ghrelin O-Acyl Transferase: Bridging Ghrelin and Energy Homeostasis

International Journal of Peptides ◽

10.1155/2011/217957 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 10

Author(s):

Andrew Shlimun ◽

Suraj Unniappan

Keyword(s):

Energy Homeostasis ◽

Expression Patterns ◽

Tissue Expression ◽

Whole Body ◽

Acyl Transferase ◽

Glucose Levels ◽

Metabolic Functions ◽

Blood Glucose Levels ◽

Body Energy ◽

Metabolic Hormone

Ghrelin O-acyl transferase (GOAT) is a recently identified enzyme responsible for the unique n-acyl modification of ghrelin, a multifunctional metabolic hormone. GOAT structure and activity appears to be conserved from fish to man. Since the acyl modification is critical for most of the biological actions of ghrelin, especially metabolic functions, GOAT emerged as a very important molecule of interest. The research on GOAT is on the rise, and several important results reiterating its significance have been reported. Notable among these discoveries are the identification of GOAT tissue expression patterns, effects on insulin secretion, blood glucose levels, feeding, body weight, and metabolism. Several attempts have been made to design and test synthetic compounds that can modulate endogenous GOAT, which could turn beneficial in favorably regulating whole body energy homeostasis. This paper will focus to provide an update on recent advances in GOAT research and its broader implications in the regulation of energy balance.

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Angiopoietin-Like Growth Factor Involved in Leptin Signaling in the Hypothalamus

International Journal of Molecular Sciences ◽

10.3390/ijms22073443 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3443

Author(s):

Yunseon Jang ◽

Jun Young Heo ◽

Min Joung Lee ◽

Jiebo Zhu ◽

Changjun Seo ◽

...

Keyword(s):

Growth Factor ◽

Brain Regions ◽

Whole Body ◽

Signal Transducers ◽

Leptin Signaling ◽

Stat3 Phosphorylation ◽

Hypothalamic Regulation ◽

Induced Signal ◽

Body Energy ◽

Transcription 3

The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons.

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Regulation of skeletal muscle energy/nutrient-sensing pathways during metabolic adaptation to fasting in healthy humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00215.2014 ◽

2014 ◽

Vol 307 (10) ◽

pp. E885-E895 ◽

Cited By ~ 17

Author(s):

Marjolein A. Wijngaarden ◽

Leontine E. H. Bakker ◽

Gerard C. van der Zon ◽

Peter A. C. 't Hoen ◽

Ko Willems van Dijk ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Lipid Oxidation ◽

Energy Homeostasis ◽

Nutrient Sensing ◽

Whole Body ◽

Metabolic Adaptation ◽

Protein Kinase Activity ◽

Short Term ◽

Muscle Energy

During fasting, rapid metabolic adaptations are required to maintain energy homeostasis. This occurs by a coordinated regulation of energy/nutrient-sensing pathways leading to transcriptional activation and repression of specific sets of genes. The aim of the study was to investigate how short-term fasting affects whole body energy homeostasis and skeletal muscle energy/nutrient-sensing pathways and transcriptome in humans. For this purpose, 12 young healthy men were studied during a 24-h fast. Whole body glucose/lipid oxidation rates were determined by indirect calorimetry, and blood and skeletal muscle biopsies were collected and analyzed at baseline and after 10 and 24 h of fasting. As expected, fasting induced a time-dependent decrease in plasma insulin and leptin levels, whereas levels of ketone bodies and free fatty acids increased. This was associated with a metabolic shift from glucose toward lipid oxidation. At the molecular level, activation of the protein kinase B (PKB/Akt) and mammalian target of rapamycin pathways was time-dependently reduced in skeletal muscle during fasting, whereas the AMP-activated protein kinase activity remained unaffected. Furthermore, we report some changes in the phosphorylation and/or content of forkhead protein 1, sirtuin 1, and class IIa histone deacetylase 4, suggesting that these pathways might be involved in the transcriptional adaptation to fasting. Finally, transcriptome profiling identified genes that were significantly regulated by fasting in skeletal muscle at both early and late time points. Collectively, our study provides a comprehensive map of the main energy/nutrient-sensing pathways and transcriptomic changes during short-term adaptation to fasting in human skeletal muscle.

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Exercise and MEF2–HDAC interactions

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-082 ◽

2007 ◽

Vol 32 (5) ◽

pp. 852-856 ◽

Cited By ~ 21

Author(s):

Sean L. McGee

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Nuclear Export ◽

Energy Homeostasis ◽

Whole Body ◽

Positive Health ◽

Exercise Induced ◽

Amp Activated Protein Kinase ◽

Body Energy ◽

Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

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Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

10.1101/749929 ◽

2019 ◽

Author(s):

Ana M. Cruz ◽

Yasaman Malekizadeh ◽

Julia M. Vlachaki Walker ◽

Paul G. Weightman Potter ◽

Katherine Pye ◽

...

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Ventromedial Hypothalamus ◽

Whole Body ◽

Ampk Activation ◽

Autonomic Nervous ◽

Glucose Levels

ABSTRACTAMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production. Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps. Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemic-hypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

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Energy Metabolism of Bone

Toxicologic Pathology ◽

10.1177/0192623317737065 ◽

2017 ◽

Vol 45 (7) ◽

pp. 887-893 ◽

Cited By ~ 10

Author(s):

Katherine J. Motyl ◽

Anyonya R. Guntur ◽

Adriana Lelis Carvalho ◽

Clifford J. Rosen

Keyword(s):

Bone Remodeling ◽

Energy Homeostasis ◽

Bone Structure ◽

Bone Cells ◽

Bone Cell ◽

Whole Body ◽

Blood Calcium ◽

Micro Cracks ◽

Intimate Link ◽

Body Energy

Biological processes utilize energy and therefore must be prioritized based on fuel availability. Bone is no exception to this, and the benefit of remodeling when necessary outweighs the energy costs. Bone remodeling is important for maintaining blood calcium homeostasis, repairing micro cracks and fractures, and modifying bone structure so that it is better suited to withstand loading demands. Osteoclasts, osteoblasts, and osteocytes are the primary cells responsible for bone remodeling, although bone marrow adipocytes and other cells may also play an indirect role. There is a renewed interest in bone cell energetics because of the potential for these processes to be targeted for osteoporosis therapies. In contrast, due to the intimate link between bone and energy homeostasis, pharmaceuticals that treat metabolic disease or have metabolic side effects often have deleterious bone consequences. In this brief review, we will introduce osteoporosis, discuss how bone cells utilize energy to function, evidence for bone regulating whole body energy homeostasis, and some of the unanswered questions and opportunities for further research in the field.

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Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0135 ◽

2020 ◽

Vol 375 (1793) ◽

pp. 20190135 ◽

Cited By ~ 3

Author(s):

Naresh C. Bal ◽

Muthu Periasamy

Keyword(s):

Energy Homeostasis ◽

Atp Hydrolysis ◽

Calcium Atpase ◽

Whole Body ◽

Signalling Molecule ◽

Brown Adipose ◽

Pump Activity ◽

Body Energy ◽

Shivering Thermogenesis

Thermogenesis in endotherms relies on both shivering and non-shivering thermogenesis (NST). The role of brown adipose tissue (BAT) in NST is well recognized, but the role of muscle-based NST has been contested. However, recent studies have provided substantial evidence for the importance of muscle-based NST in mammals. This review focuses primarily on the role of sarcoplasmic reticulum (SR) Ca 2+ -cycling in muscle NST; specifically, it will discuss recent data showing how uncoupling of sarcoendoplasmic reticulum calcium ATPase (SERCA) (inhibition of Ca 2+ transport but not ATP hydrolysis) by sarcolipin (SLN) results in futile SERCA pump activity, increased ATP hydrolysis and heat production contributing to muscle NST. It will also critically examine how activation of muscle NST can be an important factor in regulating metabolic rate and whole-body energy homeostasis. In this regard, SLN has emerged as a powerful signalling molecule to promote mitochondrial biogenesis and oxidative metabolism in muscle. Furthermore, we will discuss the functional interplay between BAT and muscle, especially with respect to how reduced BAT function in mammals could be compensated by muscle-based NST. Based on the existing data, we argue that SLN-mediated thermogenesis is an integral part of muscle NST and that muscle NST potentially contributed to the evolution of endothermy within the vertebrate clade. This article is part of the theme issue ‘Vertebrate palaeophysiology’.

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Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909917116 ◽

2019 ◽

Vol 116 (47) ◽

pp. 23822-23828 ◽

Cited By ~ 8

Author(s):

Shintaro Yamaguchi ◽

Michael P. Franczyk ◽

Maria Chondronikola ◽

Nathan Qi ◽

Subhadra C. Gunawardana ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Cold Exposure ◽

Energy Homeostasis ◽

Lipolytic Activity ◽

Whole Body ◽

Brown Adipocyte ◽

Nicotinamide Phosphoribosyltransferase ◽

Adaptive Thermogenesis ◽

Body Energy

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+–SIRT1–caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

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