Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity

Abstract

Obesity is associated with a decrease in energy expenditure relative to energy intake. The decrease in physical activity associated with obesity in several species, including humans, contributes to decreased energy expenditure. Several hormones and neuropeptides that affect appetite also modulate physical activity, including neuromedin U (NMU), a peptide found in the gut and brain. We have demonstrated that NMU microinjected into the hypothalamic paraventricular nucleus (PVN) in rats increases the energy expenditure associated with physical activity, called non-exercise activity thermogenesis (NEAT). Here we examined whether obesity in rats is related to decreased sensitivity of the PVN to the locomotor-activating effect of NMU. Diet-induced obese (DIO) rats and lean, dietresistant (DR) rats were given PVN microinjections of increasing doses of NMU both before and after one month on a high-fat diet. We found that NMU increases physical activity, energy expenditure, and NEAT in a dose-dependent manner in both DR and DIO rats, both before and after one month on the high-fat diet. Before high-fat feeding, the obesity-prone and lean rats showed similar levels of physical activity after intra-PVN microinjections of NMU. After one month of the high-fat diet, however, the obesity-resistant rats showed significantly more NMU-induced physical activity compared to the obese DIO rats. Taken together with previous studies, these results suggest that obesity may represent a state associated with decreased central sensitivity to neuropeptides such as NMU that increase physical activity and therefore energy expenditure.

Neuroregulation of nonexercise activity thermogenesis and obesity resistance

“…Spontaneous physical activity in animals is measured in a variety of ways, including videotaped recordings of behavior, telemetry (implanted transmitter signaling a nearby receiver that records the animals location), and placing animals in open-field chambers (after 24 -48 h habituation) equipped with sets of infrared beams around the chamber, such that movement can be detected in all axes (when the animal crosses one of these beams a "beam interruption" or "break" occurs) (6,19,53,56,67,96,102,108,109,117,149,156,159,160,162). The sensitivity, accuracy, and time demand of each method varies, and in our work we use an open-field chamber equipped with infrared beams, as we feel this provides the most sensitive, accurate, and feasible readings.…”

Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

“…treatment with NMU; these include the most common hypothalamic nuclei associated with NMU—PVH, Arc, dorsomedial nucleus, and lateral hypothalamic area—but also forebrain regions associated with motivation and reward (amygdala, nucleus accumbens, frontal cortex), the supraoptic nucleus, and the hindbrain parabrachial nucleus and nucleus of the solitary tract (197-199). Though the hypothalamic regions and, to a lesser extent, the hindbrain regions, have received attention in functional behavioral or physiological studies (188, 200-206), relatively little attention is paid to the potential functions of neuromedins in the forebrain.…”

“…Activation of neuromedin receptors decreases food intake and increases energy expenditure and physical activity (107, 190, 200, 201, 203, 207). Moreover, commonalities in the behavioral and energetic actions of neuromedins and homologous peptides can be seen in non-mammals, even invertebrates (208-214).…”

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

“…ICV administration of NMU reduces food intake in mice [73] and rats [72]. NMU administration also increases both physical activity and non-exercise activity thermogenesis in both DIO and lean rats [74]. NMU null mice display hyperphagia, increased body weight and adiposity, and decreased locomotor activity and energy expenditure, suggesting a role for this peptide in the regulation of energy homeostasis [75].…”