Abstract
Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding.Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch +/+ or pmch −/− rats. However, acute administration of MCH to the AcbSh of adult pmch −/− rats elevated feeding behavior towards wild type levels. Finally, adult pmch −/− rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system.Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption.
Highlights
The Melanin-Concentrating Hormone (MCH) precursor (Pmch) is predominantly expressed in neurons of the lateral hypothalamus (LHA) and the incerto hypothalamic area, which project throughout the brain [1,2,3]
To investigate in more detail which elements of feeding behavior are changed during the observed hypophagia, we performed a meal structure analysis in pmch+/+ and pmch2/2 rats at postnatal day (PND) 40, 58, 70, 84, and 98 (Figs. 1A – I)
Some parameters were affected at individual time points, robust effects after chronic loss of Pmch in the rat were only observed for body weight, food intake, and average meal size
Summary
The Melanin-Concentrating Hormone (MCH) precursor (Pmch) is predominantly expressed in neurons of the lateral hypothalamus (LHA) and the incerto hypothalamic area (sometimes referred to as zona incerta), which project throughout the brain [1,2,3]. Pmch processing generates glycine-glutamic acid (NGE), glutamic acidisoleucine (NEI), and MCH [4]. MCH, a 19-amino acid cyclic peptide, is a key regulator of food intake and metabolism; Pmch mRNA is upregulated after fasting [5,6], Pmch-deficient (pmch2/2) rodents are hypophagic, lean, and have a decreased body weight as compared to wild type siblings [7,8,9], whereas Pmch overexpression results in hyperphagia and obesity [10]. Mch1rdeficient mice are lean, hyperphagic, and hyperactive [22,23], central blockade of MCH1R lowers body weight and food intake through several mechanisms [24,25,26], and acute central MCH1R-blockade decreases high-fat food-reinforced operant responding [27]
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