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: 2.64). 10/2012; 46(6). DOI: 10.1016/j.npep.2012.09.002
Source: PubMed


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.

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    • "The hypothalamus is a major center for integrating nutritionally relevant information that originates from all peripheral organs and that is mediated through circulating hormones and metabolites and/or neural pathways (Lenard and Berthoud, 2008). The regions of the hypothalamus that regulate food intake include the arcuate (ARC), dorsomedial (DMH) (Bi et al., 2012), ventromedial (VMH) paraventricular nuclei (PVN) (Rothman et al., 2012). In these nuclei, BDNF and its high-affinity TrkB receptor are highly expressed and play a major modulatory role in controlling appetite. "
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    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 · 2.64 Impact Factor
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    • "Energy imbalance – essentially a combination of increased food intake with decreased energy expenditure – causes obesity [3], [10]. Circulating hormones, such as insulin and leptin, are readouts of the body’s energy state and act at the hypothalamus to affect food intake [3], [11]–[15]. Ideally, energy intake is equal to energy expenditure, leading to weight homeostasis. However, if not enough energy is released proportional to calories consumed, the excess energy is stored as lipid in adipocytes and weight gain ensues [13]. "
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    ABSTRACT: Obesity is a risk factor for many human diseases. However, the underlying molecular causes of obesity are not well understood. Here, we report that protein tyrosine phosphatase receptor T (PTPRT) knockout mice are resistant to high-fat diet-induced obesity. Those mice avoid many deleterious side effects of high-fat diet-induced obesity, displaying improved peripheral insulin sensitivity, lower blood glucose and insulin levels. Compared to wild type littermates, PTPRT knockout mice show reduced food intake. Consistently, STAT3 phosphorylation is up-regulated in the hypothalamus of PTPRT knockout mice. These studies implicate PTPRT-modulated STAT3 signaling in the regulation of high-fat diet-induced obesity.
    PLoS ONE 06/2014; 9(6):e100783. DOI:10.1371/journal.pone.0100783 · 3.23 Impact Factor
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    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; 121. DOI:10.1016/j.physbeh.2013.03.022 · 2.98 Impact Factor
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