Dorsomedial hypothalamic NPY and energy balance control

Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: .
Neuropeptides (Impact Factor: 2.55). 10/2012; 46(6). DOI: 10.1016/j.npep.2012.09.002
Source: PubMed

ABSTRACT Neuropeptide Y (NPY) is a potent hypothalamic orexigenic peptide. Within the hypothalamus, Npy is primarily expressed in the arcuate nucleus (ARC) and the dorsomedial hypothalamus (DMH). While the actions of ARC NPY in energy balance control have been well studied, a role for DMH NPY is still being unraveled. In contrast to ARC NPY that serves as one of downstream mediators of actions of leptin in maintaining energy homeostasis, DMH NPY is not under the control of leptin. Npy gene expression in the DMH is regulated by brain cholecystokinin (CCK) and other yet to be identified molecules. The findings of DMH NPY overexpression or induction in animals with increased energy demands and in certain rodent models of obesity implicate a role for DMH NPY in maintaining energy homeostasis. In support of this view, adeno-associated virus (AAV)-mediated overexpression of NPY in the DMH causes increases in food intake and body weight and exacerbates high-fat diet-induced hyperphagia and obesity. Knockdown of NPY in the DMH via AAV-mediated RNAi ameliorates hyperphagia, obesity and glucose intolerance of Otsuka Long-Evans Tokushima Fatty rats in which DMH NPY overexpression has been proposed to play a causal role. NPY knockdown in the DMH also prevents high-fat diet-induced hyperphagia, obesity and impaired glucose homeostasis. A detailed examination of actions of DMH NPY reveals that DMH NPY specifically affects nocturnal meal size and produces an inhibitory action on within meal satiety signals. In addition, DMH NPY modulates energy expenditure likely through affecting brown adipocyte formation and thermogenic activity. Overall, the recent findings provide clear evidence demonstrating critical roles for DMH NPY in energy balance control, and also imply a potential role for DMH NPY in maintaining glucose homeostasis.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic stress, whether associated with obesity or not, leads to different neuroendocrine and psychological changes. Obesity or being overweight has become one of the most serious worldwide public health problems. Additionally, it is related to a substantial increase in daily energy intake, which results in substituting nutritionally adequate meals for snacks. This metabolic disorder can lead to morbidity, mortality, and reduced quality of life. On the other hand, brain-derived neurotrophic factor (BDNF) is widely expressed in all brain regions, particularly in the hypothalamus, where it has important effects on neuroprotection, synaptic plasticity, mammalian food intake-behavior, and energy metabolism. BDNF is involved in many activities modulated by the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, this study aims to evaluate the effect of obesity associated with chronic stress on the BDNF central levels of rats. Obesity was controlled by analyzing the animals' caloric intake and changes in body weight. As a stress parameter, we analyzed the relative adrenal gland weight. We found that exposure to chronic restraint stress during 12 weeks increases the adrenal gland weight, decreases the BDNF levels in the hippocampus and is associated with a decrease in the calorie and sucrose intake, characterizing anhedonia. These effects can be related stress, a phenomenon that induces depression-like behavior. On the other hand, the rats that received the hypercaloric diet had an increase in calorie intake and became obese, which was associated with a decrease in hypothalamus BDNF levels. Copyright © 2015. Published by Elsevier Ltd.
    Neuropeptides 02/2015; 51. DOI:10.1016/j.npep.2015.01.002 · 2.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In addition to controlling food intake, the dorsomedial hypothalamus (DMH) plays an important role in thermoregulation. Within the DMH, a number of neuropeptides and receptors have been found and their roles in controlling energy balance are being investigated. We recently found that the orexigenic neuropeptide Y (NPY) in the DMH has specific actions on body adiposity and thermogenesis using a viral-mediated manipulation of NPY in the DMH. Knockdown of NPY in the DMH promotes the development of brown adipocytes in white adipose tissue and increases brown adipocyte activity. DMH NPY knockdown also causes increased thermogenesis and energy expenditure. Finally, DMH NPY knockdown prevents high-fat diet-induced obesity and improves glucose homeostasis. This review focuses on the role of DMH NPY in modulating body adiposity and thermogenesis.
    Physiology & Behavior 04/2013; DOI:10.1016/j.physbeh.2013.03.022 · 3.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES: To determine a role for NPY overexpression in the dorsomedial hypothalamus (DMH) in obesity etiology using the rat model of adeno-associated virus (AAV)-mediated expression of NPY (AAVNPY) in the DMH. DESIGN AND METHODS: Rats received bilateral DMH injections of AAVNPY or control vector and were fed on regular chow. Five weeks post-viral injection, half the rats from each group were switched to access to a high-fat diet for another 11 weeks. We examined variables including body weight, food intake, energy efficiency, meal patterns, glucose tolerance, fat mass, plasma insulin, plasma leptin, and hypothalamic gene expression. RESULTS: Rats with DMH NPY overexpression had increased food intake and body weight and lowered metabolic efficiency. The hyperphagia was mediated through increased meal size during the dark. Although these rats had normal blood glucose, their plasma insulin levels were increased in both basal and glucose challenge conditions. While high-fat diet induced hyperphagia, obesity, and hyperinsulinemia, these effects were amplified in rats with DMH NPY overexpression. Arcuate Npy, agouti-related protein and proopiomelanocortin expression was appropriately regulated in response to positive energy balance. CONCLUSION: These results indicate that DMH NPY overexpression can cause hyperphagia and obesity and DMH NPY may have actions in glucose homeostasis.
    Obesity 06/2013; 21(6). DOI:10.1002/oby.20467 · 4.39 Impact Factor