Regulation of Peripheral Metabolism by Substrate Partitioning in the Brain

Moreno, Cesar; Yang, Linda; Dacks, Penny A.; Isoda, Fumiko; Poplawski, Michael; Mobbs, Charles V.

doi:10.1016/j.ecl.2012.11.007

Cited by 7 publications

(10 citation statements)

References 115 publications

(152 reference statements)

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“…Interestingly, free fatty acids (FFAs) oppose the effects of glucose on hypothalamic neuronal activity, an observation consistent with the hypothesis that glucose serves as a positive signal of nutritional resources whereas FFAs, which are released during fasting, serves as a negative signal of nutritional resources [38]. The physiological significance of these glucose-sensing neurons was demonstrated by the observation that infusion of the glycolytic inhibitor 2-deoxyglucose produces a rapid and robust increase in epinephrine and glucagon that act to increase blood glucose [39], whereas infusion of glucose into the same area prevents these counterregulatory responses to whole-body hypoglycemia [40].…”

Section: Vmh Neurons Determine Glucose Homeostasis Energy Balance Asupporting

confidence: 62%

Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

Mobbs

Moreno

Poplawski

2013

Trends in Endocrinology & Metabolism

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We propose that energy balance, glucose homeostasis, and aging are all regulated largely by the same nutrient-sensing neurons in the ventromedial hypothalamus (VMH)., Although the central role of these neurons in regulating energy balance is clear, their role in regulating glucose homeostasis has only become more clear recently. It is the latter function that may be most relevant to aging and lifespan, by controlling the rate of glucose metabolism. Specifically, glucose-sensing neurons in VMH promote peripheral glucose metabolism, and dietary restriction, by reducing glucose metabolism in these neurons, reduces glucose metabolism of the rest of the body, thereby increasing lifespan. Here we discuss recent studies demonstrating the key role of hypothalamic neurons in driving aging and age-related diseases.

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Section: Vmh Neurons Determine Glucose Homeostasis Energy Balance Asupporting

confidence: 62%

Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

Mobbs

Moreno

Poplawski

2013

Trends in Endocrinology & Metabolism

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“…Remarkably, inhibition of hypothalamic Cbp reduced expression of genes implicated in all three of the main systems that sense nutritional status (e.g., glucokinase, the leptin receptor, and insulin receptor substrate). Furthermore inhibition of Cbp appeared to promote a switch from hypothalamic glucose metabolism toward lipid metabolism, which could plausibly promote obese phenotypes [6]. These studies test the hypothesis that the obese and diabetic phenotypes produced by inhibition of Cbp may be mediated in part by induction of Cpt1a .…”

Section: Discussionmentioning

confidence: 81%

“…Nutrient sensing of metabolic status and homeostasis can be largely attributed to hypothalamic responses, and failure of such mechanisms plausibly promotes obese phenotypes [6]. Whole body Cbp deletion is embryonic lethal, and while Cbp heterozygous knockout mice are viable, these animals exhibit developmental complications resulting in distinct phenotypes such as craniofacial malformations, and decreased body weight [35].…”

Section: Discussionmentioning

confidence: 99%

“…Hypothalamic glucose sensing neurons have long been hypothesized to play a role in regulating energy balance [5], but the role of these neurons in regulating energy balance remains to be determined. Nevertheless recent studies have suggested that a metabolic shift away from hypothalamic glucose metabolism and toward hypothalamic lipid metabolism promotes obese phenotypes [6,7]. …”

Section: Introductionmentioning

confidence: 99%

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Role of Hypothalamic Creb-Binding Protein in Obesity and Molecular Reprogramming of Metabolic Substrates

et al. 2016

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We have reported a correlation between hypothalamic expression of Creb-binding protein (Cbp) and lifespan, and that inhibition of Cbp prevents protective effects of dietary restriction during aging, suggesting that hypothalamic Cbp plays a role in responses to nutritional status and energy balance. Recent GWAS and network analyses have also implicated Cbp as the most connected gene in protein-protein interactions in human Type 2 diabetes. The present studies address mechanisms mediating the role of Cbp in diabetes by inhibiting hypothalamic Cbp using a Cre-lox strategy. Inhibition of hypothalamic Cbp results in profound obesity and impaired glucose homeostasis, increased food intake, and decreased body temperature. In addition, these changes are accompanied by molecular evidence in the hypothalamus for impaired leptin and insulin signaling, a shift from glucose to lipid metabolism, and decreased Pomc mRNA, with no effect on locomotion. Further assessment of the significance of the metabolic switch demonstrated that enhanced expression of hypothalamic Cpt1a, which promotes lipid metabolism, similarly resulted in increased body weight and reduced Pomc mRNA.

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“…DR also induced genes expected to reduce glucose metabolism (e.g., Gsk3 and Pdk1 ) and promote fatty acid metabolism (e.g., Crot , Crat , Acox3 , and Acox1 ) independently of the transgene, and consistent with effects of fasting (Poplawski et al, 2010). We have previously observed changes in gene expression that indicate a switch in substrate utilization in other interventions resulting in energy deficit (Moreno et al, 2013; Poplawski et al, 2010). Yet surprisingly in the present study many of these metabolic markers (e.g.…”

Section: Resultsmentioning

confidence: 99%

Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT

Moreno

Ehrlich

Mobbs

2016

Neurobiology of Disease

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Huntington’s disease (HD) is a fatal neurodegenerative disease characterized by metabolic, cognitive, and motor deficits. HD is caused by an expanded CAG repeat in the first exon of the HTT gene, resulting in an expanded polyglutamine section. Dietary restriction (DR) increases lifespan and ameliorates age-related pathologies, including in a model of HD, but the mechanisms mediating these protective effects are unknown. We report metabolic and behavioral effects of DR in the full-length YAC128 HD mouse model, and associated transcriptional changes in hypothalamus and striatum. DR corrected many effects of the transgene including increased body weight, decreased blood glucose, and impaired motor function. These changes were associated with reduced striatal human (but not mouse) HTT expression, as well as alteration in gene expression regulating histone acetylation modifications, particularly Hdac2. Other mRNAs related to Huntington’s pathology in striatal tissue showed significant modulation by the transgene, dietary restriction or both. These results establish a protective role of DR in a transgenic model that contains the complete human HTT gene and for the first time suggest a role for DR in lowering HTT level, which correlates with severity of symptoms.

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Regulation of Peripheral Metabolism by Substrate Partitioning in the Brain

Cited by 7 publications

References 115 publications

Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

Role of Hypothalamic Creb-Binding Protein in Obesity and Molecular Reprogramming of Metabolic Substrates

Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT

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