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1.
Nat Commun ; 10(1): 311, 2019 01 18.
Article in English | MEDLINE | ID: mdl-30659173

ABSTRACT

The type of nutrient utilized by the organism at any given time-substrate utilization-is a critical component of energy metabolism. The neuronal mechanisms involved in the regulation of substrate utilization in mammals are largely unknown. Here, we found that activation of hypothalamic Agrp neurons rapidly altered whole-body substrate utilization, increasing carbohydrate utilization, while decreasing fat utilization. These metabolic changes occurred even in the absence of caloric ingestion and were coupled to increased lipogenesis. Accordingly, inhibition of fatty acid synthase-a key enzyme that mediates lipogenesis-blunted the effects of Agrp neuron activation on substrate utilization. In pair-fed conditions during positive energy balance, activation of Agrp neurons improved metabolic efficiency, and increased weight gain and adiposity. Conversely, ablation of Agrp neurons impaired fat mass accumulation. These results suggest Agrp neurons regulate substrate utilization, contributing to lipogenesis and fat mass accumulation during positive energy balance.


Subject(s)
Adiposity/physiology , Agouti-Related Protein/metabolism , Carbohydrate Metabolism , Neurons/metabolism , Animals , Capsaicin/pharmacology , Energy Metabolism/physiology , Hypothalamus/metabolism , Lipogenesis/physiology , Mice , Mice, Knockout , Neurons/drug effects , Weight Gain/physiology
2.
Adipocyte ; 6(3): 224-233, 2017 07 03.
Article in English | MEDLINE | ID: mdl-28792785

ABSTRACT

Over the past 2 decades, the incidence of childhood obesity has risen dramatically. This recent rise in childhood obesity is particularly concerning as adults who were obese during childhood develop type II diabetes that is intractable to current forms of treatment compared with individuals who develop obesity in adulthood. While the mechanisms responsible for the exacerbated diabetic phenotype associated with childhood obesity is not clear, it is well known that childhood is an important time period for the establishment of normal white adipose tissue in humans. This association suggests that exposure to obesogenic stimuli during adipose development may have detrimental effects on adipose function and metabolic homeostasis. In this study, we identify the period of development associated with puberty, postnatal days 18-34, as critical for the establishment of normal adipose mass in mice. Exposure of mice to high fat diet only during this time period results in metabolic dysfunction, increased leptin expression, and increased adipocyte size in adulthood in the absence of sustained increased fat mass or body weight. These findings indicate that exposure to obesogenic stimuli during critical developmental periods have prolonged effects on adipose tissue function that may contribute to the exacerbated metabolic dysfunctions associated with childhood obesity.


Subject(s)
Adipose Tissue, White/metabolism , Puberty/physiology , Adipocytes/metabolism , Adipose Tissue/metabolism , Adipose Tissue, White/physiology , Adiposity/physiology , Animals , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Female , Homeostasis/physiology , Humans , Leptin/metabolism , Male , Mice , Obesity/metabolism , Puberty/metabolism
4.
Cell ; 160(6): 1222-32, 2015 Mar 12.
Article in English | MEDLINE | ID: mdl-25748653

ABSTRACT

The nervous system evolved to coordinate flexible goal-directed behaviors by integrating interoceptive and sensory information. Hypothalamic Agrp neurons are known to be crucial for feeding behavior. Here, however, we show that these neurons also orchestrate other complex behaviors in adult mice. Activation of Agrp neurons in the absence of food triggers foraging and repetitive behaviors, which are reverted by food consumption. These stereotypic behaviors that are triggered by Agrp neurons are coupled with decreased anxiety. NPY5 receptor signaling is necessary to mediate the repetitive behaviors after Agrp neuron activation while having minor effects on feeding. Thus, we have unmasked a functional role for Agrp neurons in controlling repetitive behaviors mediated, at least in part, by neuropeptidergic signaling. The findings reveal a new set of behaviors coupled to the energy homeostasis circuit and suggest potential therapeutic avenues for diseases with stereotypic behaviors.


Subject(s)
Hypothalamus/physiology , Neurons/physiology , Stereotyped Behavior , Agouti-Related Protein/metabolism , Animals , Anxiety/metabolism , Behavior, Animal/drug effects , Capsaicin/administration & dosage , Feeding Behavior/drug effects , Female , GABA Antagonists/administration & dosage , Hypothalamus/cytology , Male , Neurons/classification , Stereotyped Behavior/drug effects , TRPV Cation Channels/metabolism
5.
Nat Neurosci ; 15(8): 1108-10, 2012 Jun 24.
Article in English | MEDLINE | ID: mdl-22729177

ABSTRACT

It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit-impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing-dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors.


Subject(s)
Agouti-Related Protein/physiology , Behavior, Animal/physiology , Cocaine/pharmacology , Dopaminergic Neurons/physiology , Long-Term Potentiation/physiology , Neuronal Plasticity/physiology , Neurons/physiology , Animals , Dopamine , Female , Gene Knockdown Techniques , Mice , Mice, Transgenic , Reward
6.
Biol Psychiatry ; 67(2): 168-74, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19811775

ABSTRACT

BACKGROUND: Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in female subjects is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant desipramine. Considering that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life might influence behavioral and synaptic responses to stress and depression. METHODS: With electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats (n = 70), under different conditions of estradiol exposure. RESULTS: Stress induced an acute and persistent loss of hippocampal spine synapses, whereas subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either before stress or before escape testing of nonstressed animals increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers. CONCLUSIONS: These findings suggest that hippocampal spine synapse remodeling might be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression.


Subject(s)
CA1 Region, Hippocampal/cytology , Dendritic Spines/drug effects , Estradiol/pharmacology , Estrogens/pharmacology , Helplessness, Learned , Neurons/cytology , Analysis of Variance , Animals , Behavior, Animal/drug effects , Dendritic Spines/ultrastructure , Disease Models, Animal , Electroshock/adverse effects , Escape Reaction/drug effects , Female , Microscopy, Electron, Transmission/methods , Neurons/drug effects , Ovariectomy/methods , Rats , Rats, Sprague-Dawley , Regression Analysis , Stereotaxic Techniques , Stress, Psychological/complications , Stress, Psychological/etiology , Stress, Psychological/pathology , Synapses/drug effects , Synapses/ultrastructure , Time Factors
7.
Mol Ther ; 18(3): 588-93, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20010918

ABSTRACT

Vectors derived from adeno-associated virus (AAV) are promising candidates for neural cell transduction in vivo because they are nonpathogenic and achieve long-term transduction in the central nervous system. AAV serotype 2 (AAV2) is the most widely used AAV vector in clinical trials based largely on its ability to transduce neural cells in the rodent and primate brain. Prior work in rodents suggests that other serotypes might be more efficient; however, a systematic evaluation of vector transduction efficiency has not yet been performed in the primate brain. In this study, AAV viral vectors of serotypes 1-6 with an enhanced green-fluorescent protein (GFP) reporter gene were generated at comparable titers, and injected in equal amounts into the brains of Chlorocebus sabaeus. Vector injections were placed in the substantia nigra (SN) and the caudate nucleus (CD). One month after injection, immunohistochemistry for GFP was performed and the total number of GFP+ cells was calculated using unbiased stereology. AAV5 was the most efficient vector, not only transducing significantly more cells than any other serotype, but also transducing both NeuN+ and glial-fibrillary-acidic protein positive (GFAP+) cells. These results suggest that AAV5 is a more effective vector than AAV2 at delivering potentially therapeutic transgenes to the nigrostriatal system of the primate brain.


Subject(s)
Corpus Striatum/metabolism , Dependovirus/metabolism , Substantia Nigra/metabolism , Animals , Brain/metabolism , Cell Line , Gene Transfer Techniques , Genetic Vectors , Green Fluorescent Proteins/metabolism , Humans , Immunohistochemistry/methods , Microscopy, Confocal , Neurons/metabolism , Primates
8.
Proc Natl Acad Sci U S A ; 105(37): 14187-91, 2008 Sep 16.
Article in English | MEDLINE | ID: mdl-18768812

ABSTRACT

Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agency's reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage.


Subject(s)
Estradiol/blood , Hippocampus/drug effects , Hippocampus/metabolism , Phenols/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Synapses/metabolism , Animals , Benzhydryl Compounds , Chlorocebus aethiops , Female , Ovariectomy , Spine/drug effects , Synapses/drug effects
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