Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice

Abstract

Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O 2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide.

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

“…We found that increased NMU in the xenograft tumors were associated with cancer cachexia in mice. NMU itself has an anorexigenic effect in animals (Howard et al, 2000;Hanada et al, 2004;Shousha et al, 2006), and transgenic overexpression of it promotes leanness in mice (Kowalski et al, 2005). As NMU can function as a proinflammatory mediator by promoting interleukin (IL)-6 production in Th2-type T cells or macrophages (Johnson et al, 2004;Moriyama et al, 2006) and inhibition of IL-6 can partially attenuate or reverse cancer cachexia (Strassmann and Kambayashi, 1995), this might be a mechanism underlying NMU-mediated cancer cachexia.…”

Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis

“…injection of NMU gives a clear catabolic response, increasing core body temperature and locomotor activity, reducing food intake (Nakazato et al 2000) and acute administration of NMU into the PVN has clear anorexigenic effects (Wren et al 2002); however, chronic injections of NMU into the PVN have no effect on food intake or body weight. Nevertheless, the NMU knockout mouse shows clear hyperphagia and obesity ) and the transgenic mouse overexpressing NMU is lean and hypophagic (Kowalski et al 2005). Recently, it has been demonstrated that at least some of the effects of leptin are mediated via NMU (Jethwa et al 2005).…”

“…It is also involved in the regulation of circadian rhythmicity (Nakahara et al 2004) and luteinizing hormone secretion (Quan et al 2003). The NMU knockout mouse is hyperphagic and obese , while the transgenic mouse, overexpressing NMU, is lean and hypophagic (Kowalski et al 2005) providing strong support for the role of NMU in energy balance.…”

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

“…These mice also develop late-onset hyperglycemia and hyperlipidemia [75]. Transgenic mice that overexpress NMU are hypophagic, and have reduced body weight, low somatic and liver fat, and improved insulin sensitivity [76]. On a high fat diet, these mice remain lighter than wild types and eat less [76].…”

“…Transgenic mice that overexpress NMU are hypophagic, and have reduced body weight, low somatic and liver fat, and improved insulin sensitivity [76]. On a high fat diet, these mice remain lighter than wild types and eat less [76]. A variant in the human NMU gene has also been linked to obesity in the human population [77].…”