Circumventing leptin resistance for weight control.

Departments of Neuroscience and Physiology, College of Medicine, University of Florida McKnight Brain Institute, Gainesville, FL 32610-0244, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 05/2001; 98(8):4279-81. DOI: 10.1073/pnas.091101498
Source: PubMed
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    ABSTRACT: Electrophysiological studies of isolated smooth muscle cells have revealed a variety of membrane-conductance changes that contribute to depolarization and excitation. These include activation of inward Cl− and nonselective cation currents, and the suppression of several types of outward K+ currents, leading to depolarization and opening of voltage-dependent Ca2+ current. In most cases, several of these mechanisms operate together in the same cell. We now recognize that [Ca2+]u plays a critical role not only in initiating contraction but in regulating membrane-channel activity. Cl− current is Ca2+ activated, and muscarinic nonselective cation current is facilitated by Ca2+. Cl− and nonselective cation channels therefore participate in a positive feedback loop, where elevation of [Ca2+]; by entry across the membrane or by release from internal stores initiates or promotes depolarization, which in turn leads to further influx of Ca2+ through voltage-dependent Ca2+ channels. These features of excitation of smooth muscle differ from established views, where depolarization is the primary event causing Ca2+ entry and contraction.
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    ABSTRACT: Context Obese individuals tend to resist the weight-regulating effects of exog- enously administered leptin. A genetically engineered recombinant human variant cili- ary neurotrophic factor (rhvCNTF) that signals through leptinlike pathways in the hy- pothalamus has been shown to bypass leptin resistance in animal models of obesity. Objective To identify a safe and well-tolerated dose of rhvCNTF that causes weight loss in obese adults. Design, Setting, and Patients Twelve-week, double-blind, randomized, parallel- group, dose-ranging, multicenter clinical trial conducted at 2 university obesity clinics and at 5 independent clinical research clinics from March 2000 to August 2001, and including 173 nondiabetic obese adults, 82.6% of whom were women, with a mean (SD) body mass index of 41.1 (4.1). Interventions Patients were randomly assigned to receive daily for 12 weeks sub- cutaneous injections of placebo (n=32) or 0.3 µg/kg (n=32), 1.0 µg/kg (n=38), or 2.0 µg/kg (n=33) of rhvCNTF. Another group received 1.0 µg/kg for 8 weeks and placebo for 4 weeks (n=38), but they were not included in the primary analysis. All participants received instructions for a reduced-calorie diet (World Health Organiza- tion formula minus 500 kcal/d). Main Outcome Measures Change in weight during the 12-week double-blind treat- ment period and proportion of patients who achieved a weight loss of at least 5%. Results Of the 173 randomized patients, 123 (71%) completed the double-blind dosing period. Mean (SEM) changes in kilograms from baseline body weights were 0.1 (0.6) for placebo and �1.5 (0.6) for the 0.3, �4.1 (0.6) for the 1.0, and -3.4 (0.7) for the 2.0 µg/kg of rhvCNTF dosage groups (P.001, test for trend). Two patients (8.7%) in the placebo and 2 (8.3%) in the 0.3-µg/kg, 8 (29.6%) in the 1.0-µg/kg, and 5 (26%) in the 2.0-µg/kg treatment groups achieved a weight loss of at least 5%. Recombinant human variant CNTF was generally well tolerated although adverse events occurred in 75% of patients receiving placebo and 78% to 93% of patients receiving rhvCNTF, in a dose-related fashion, with mild injection site reactions as the most fre- quently reported adverse event. Conclusions In this initial, dose-ranging, 12-week study, treatment with rhvCNTF resulted in more weight loss than placebo. These preliminary findings require confir- mation in large prospective clinical trials.
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    ABSTRACT: A complex hypothalamic network of hormones and neuropeptides regulates body weight. Mutations in these hormones/peptides, their receptors or regulatory elements, have been described in humans, but they are rare and could not explain the commonest forms of obesity. Nevertheless, the study of these mutations has favored a great progress in the knowledge of genetic basis and physiopathology of obesity, opening new perspectives on the therapeutic approach of this prevalent disease. Recently, mutations in the melanocortin 4 receptor have been found in up to 5% of severe obese subjects, being thus far the most prevalent monogenic form of obesity in humans. In this revision, we discuss the mutations described in some elements of the body weight regulation system in humans, and their implications for the genesis of obesity.
    Arquivos Brasileiros de Endocrinologia & Metabologia 08/2003; 47(4):398-409. · 0.88 Impact Factor


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