Melanin-concentrating hormone (MCH) is a 19-aa cyclic neuropeptide originally isolated from chum salmon pituitaries. Besides its effects on the aggregation of melanophores in fish several lines of evidence suggest that in mammals MCH functions as a regulator of energy homeostasis. Recently, several groups reported the identification of an orphan G protein-coupled receptor as a receptor for MCH (MCH-1R). We hereby report the identification of a second human MCH receptor termed MCH-2R, which shares about 38% amino acid identity with MCH-1R. MCH-2R displayed high-affinity MCH binding, resulting in inositol phosphate turnover and release of intracellular calcium in mammalian cells. In contrast to MCH-1R, MCH-2R signaling is not sensitive to pertussis toxin and MCH-2R cannot reduce forskolin-stimulated cAMP production, suggesting an exclusive G ␣q coupling of the MCH-2R in cell-based systems. Northern blot and in situ hybridization analysis of human and monkey tissue shows that expression of MCH-2R mRNA is restricted to several regions of the brain, including the arcuate nucleus and the ventral medial hypothalamus, areas implicated in regulation of body weight. In addition, the human MCH-2R gene was mapped to the long arm of chromosome 6 at band 6q16.2-16.3, a region reported to be associated with cytogenetic abnormalities of obese patients. The characterization of a second mammalian G protein-coupled receptor for MCH potentially indicates that the control of energy homeostasis in mammals by the MCH neuropeptide system may be more complex than initially anticipated.

Several lines of epidemiological evidence have suggested that non-alcoholic steatohepatitis (NASH) is closely associated with obesity in humans. However, the precise mechanisms of the progression of NASH and its key metabolic abnormalities remain to be elucidated. We found that long-term high-fat diet (HFD) exposure induces NASH, with excess body weight, hyperinsulinemia and hypercholesteremia in mice. Longitudinal analysis of the model showed that steatohepatitis was induced after onset of metabolic abnormalities. In addition, we found that expression of MCP-1 mRNA was induced in the liver before induction of TNFalpha and type I collagen alpha1 mRNAs, and prior to onset of steatohepatitis. We confirmed that hepatic MCP-1 contents were increased in mice fed HFD for 50 weeks, although the precise role of MCP-1 in the development of NASH remains to be addressed. The mouse model was also characterized by moderate reductions in catalase activity and glutathione content, as well as by overexpression of fatty acid synthase, acetyl-CoA carboxylase 1 and FAT/CD36 mRNAs in the liver. The murine NASH model apparently mimics clinical aspects of the condition and provides insight into NASH.

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Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 microg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis.

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QRFP, an RFamide peptide, was recently identified as an endogenous ligand of an orphan G protein-coupled receptor, GPR103. Recent investigation revealed that acute intracerebroventricular (ICV) administration of QRFP26/P518/26RFa, a constitutive part of QRFP43 (43-amino acid-residue form of QRFP), increases appetite in mice, but its role in long-term energy homeostasis remains unknown. In the present study, we examined the effects of chronic administration of QRFP43 on feeding behavior, body weight regulation, and energy expenditure in mice. Intracerebroventricular infusion of QRFP43 for 13 d resulted in a significant increase in body weight and fat mass with hyperphagia. Weight gain and hyperphagia were more evident when mice were fed a moderately high-fat diet. Pair feeding of QRFP43-infused mice did not increase body weight but significantly increased fat mass and plasma concentrations of insulin, leptin, and cholesterol when compared with controls. Moreover, significant decreases in rectal temperature and expression of brown adipose tissue uncoupling protein-1 mRNA were observed in QRFP43-infused ad libitum- and pair-fed mice. The present results suggest that QRFP plays an important role in energy homeostasis by regulating appetite and energy expenditure.

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Cisplatin (CDDP) has been a key drug for chemotherapy in patients with head and neck squamous cell carcinoma. Nephrotoxicity is one of its adverse reactions that are dose limiting. To increase its antitumor effects and reduce such toxicity problems, polymeric micelles carrying CDDP (NC-6004) have been developed. The present study was designed to evaluate the efficacy and safety of NC-6004 for oral squamous cell carcinoma. In vitro antitumor activity was assayed in four oral squamous cell carcinoma cell lines. To investigate the antitumor and nephrotoxic effects of NC-6004, nude mice bearing OSC-19 were administered NC-6004 or CDDP. The in vitro growth-inhibitory effect of NC-6004 was significantly less than that of CDDP. However, both NC-6004 and CDDP showed equivalent antitumor effects in vivo. Mice with CDDP developed renal cell apoptosis; however, those injected with NC-6004 were almost free of renal cell injury. Moreover, in an orthotopic tongue cancer model using OSC-19, NC-6004 reduced the rate of sentinel lymph node metastasis to lower than that with CDDP. In conclusion, considering the potential advantages in terms of noticeable antitumor activity, lymphatic drug delivery and reduced nephrotoxicity, NC-6004 represents a significant structural improvement in the development of a platinum complex. (Cancer Sci 2013; 104: 369-374) H ead and neck cancer remains a significant public health problem and ranks in the six leading cancers by incidence worldwide, with an estimated 600 000 new cases every year.(1) Cisplatin (cis-dichlorodiammineplatinum; CDDP) has been demonstrated to be one of the most effective cytotoxic agents (2) and the CDDP-based chemotherapy regimen has gained widespread use in patients with head and neck squamous cell carcinoma (HNSCC). However, its administration has been hindered by its adverse reactions, for example, nephrotoxicity, neurotoxicity, gastrointestinal toxicity, hematological toxicity and ototoxicity.(3) Among these, the significant risk of nephrotoxicity frequently hinders the use of high doses to maximize its antineoplastic effects, which might be the cause of treatment failure.To overcome these problems and improve the therapeutic effect of CDDP, we have been applying superselective supradose intra-arterial CDDP infusion for advanced HNSCC. However, since this technique is more complicated than that of i.v. infusion of antitumor drugs, it is not prevalent in the chemotherapy scene. Recently, several kinds of nanoparticle therapeutic platforms, including liposomes, nanoparticles and polymeric micelles, have been developed based on the idea that the drug delivery system (DDS) can accumulate in the tumor selectively, with reduced distribution in normal tissues and minimized undesirable side-effects.(5-7) NC-6004, which is a CDDP-incorporating polymeric micellar nanoparticle, enhanced antitumor activity and reduced the nephrotoxicity and neurotoxicity of CDDP in gastric cancer. (8)(9)(10) Poly(ethylene glycol)-poly(glutamic acid) block copolymers (PEG-P [Gu]) confer a stealth...