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The leptin receptor is a member of the class I cytokine receptor family and is involved in the control of appetite and body weight. The predicted amino acid sequence of the extracellular region of the cloned leptin receptor differs from that of many other cytokine receptors in that it contains two homologous segments representing potential ligand binding sites. After the analysis of various deletion and substitution mutants of the leptin receptor, we found that the first potential binding motif is not required for leptin binding and receptor activation, whereas modification of the second potential binding motif can lead to inactive receptor mutants. Further deletion analysis generated a minimal binding domain that retains high affinity leptin binding. The leptin binding domain thus has been localized to residues 323-640, which contain the second segment of cytokine receptor domain/fibronectin type 3 domain (residues 428-635). Coexpression of the active isoform of leptin receptor (OB-Rb) with an inactive mutant lacking high affinity leptin binding site led to suppression of the activity mediated by OB-Rb, suggesting that the leptin receptor may exist as a multimeric complex in the absence of leptin.

Leptin administration improves skeletal muscle insulin responsiveness in diet-induced insulin-resistant rats. Am J Physiol Endocrinol Metab 280: E130-E142, 2001.-In addition to suppressing appetite, leptin may also modulate insulin secretion and action. Leptin was administered here to insulin-resistant rats to determine its effects on secretagogue-stimulated insulin release, whole body glucose disposal, and insulin-stimulated skeletal muscle glucose uptake and transport. Male Wistar rats were fed either a normal (Con) or a high-fat (HF) diet for 3 or 6 mo. HF rats were then treated with either vehicle (HF), leptin (HF-Lep, 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 sc), or food restriction (HF-FR) for 12-15 days. Glucose tolerance and skeletal muscle glucose uptake and transport were significantly impaired in HF compared with Con. Whole body glucose tolerance and rates of insulinstimulated skeletal muscle glucose uptake and transport in HF-Lep were similar to those of Con and greater than those of HF and HF-FR. The insulin secretory response to either glucose or tolbutamide (a pancreatic ␤-cell secretagogue) was not significantly diminished in HF-Lep. Total and plasma membrane skeletal muscle GLUT-4 protein concentrations were similar in Con and HF-Lep and greater than those in HF and HF-FR. The findings suggest that chronic leptin administration reversed a high-fat diet-induced insulin-resistant state, without compromising insulin secretion.ob gene product; high-fat diet; glucose tolerance; glucose uptake and transport; GLUT-4 protein LEPTIN, THE PRODUCT of the ob gene (62), has received a great deal of attention since its discovery in 1994, due to the ability of this 16-kDa protein hormone to reduce visceral adipose deposition (21,37). This biological activity is important from a public health perspective, as increases in visceral fat have been associated with "insulin resistance syndrome" or Syndrome X (39). Attenuation of insulin resistance will decrease the incidence of metabolic abnormalities such as hypertriglyceridemia, reduced high-density lipoproteins, elevated apolipoprotein B levels, and hypertension. Furthermore, reduced visceral fat deposition may also prevent the development of non-insulin-dependent diabetes (17).It is believed that leptin exerts its primary effect by acting on receptors in the hypothalamus, possibly via inhibition of neuropeptide Y release (47). However, leptin receptor isoforms are expressed in tissues other than the hypothalamus (12, 29, 51), and insulin action (e.g., phosphatidylinositol 3-kinase activity, skeletal muscle glucose uptake and transport) is improved in these tissues after leptin treatment (3,56,57,60). Improvements in insulin-stimulated glucose disposal after chronic leptin administration were initially demonstrated by Barzilai et al. (3) and Sivitz et al. (44). Barzilai et al. (3) reported that 8 days of leptin treatment increased whole body glucose uptake in SpragueDawley rats as assessed by the euglycemic clamp technique. In an extension to these findings, we (60) found that 14...

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Objectives-To determine the effect of walking on incident depressive symptoms in elderly Japanese-American men with and without chronic disease Design-Prospective cohort study Setting-The Honolulu-Asia Aging StudyParticipants-Japanese-American men aged 71 to 93 years at baseline Measurements-Physical activity was assessed by self-reported distance walked per day. Depressive symptoms were measured with an 11-question version of the Centers for Epidemiologic Studies Depression Scale (CES-D) at the 4th exam (n=3196) and again at the 7th exam 8 years later (1999-2000, n=1417). Presence of incident depressive symptoms was defined as CESD-11 score ≥ 9 or taking anti-depressants at Exam 7. Subjects with prevalent depressive symptoms at baseline were excluded. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptResults-Age adjusted 8-year incident depressive symptoms were 13.6%, 7.6% and 8.5% for low (< ¼ miles/day), intermediate (¼ to 1.5 miles/day) and high (> 1.5 miles/day) walking groups at baseline, p=0. Conclusion-Daily physical activity (≥¼ mile/day) is significantly associated with a lower risk for 8-year incident depressive symptoms in elderly Japanese-American men who do not have chronic disease at baseline.

These results support the hypothesis that alcohol-dependent individuals with a history of suicide attempts are more severely impaired. Screening and subsequent treatment of alcohol use disorder, psychiatric comorbidity, and substance use disorders among alcoholics may be crucial in preventing suicide attempts and completions.

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