Andrea de Silva

Lifestyle factors fail to explain the variation in plasma leptin concentrations in women

To assess the relationship between circulating leptin concentrations, metabolic parameters, and lifestyle factors such as alcohol intake, physical activity level, smoking habits, and reproductive history, a cohort of 359 women was drawn from a population-based study conducted in Victoria, Australia. The parameters measured included body mass index (BMI); waist and hip circumference; blood pressure; and fasting glucose, insulin, triacylglycerol, cholesterol, and leptin concentrations. In addition, a self-administered questionnaire was used to assess reproductive history, physical activity level, alcohol intake, and smoking habits. Our results demonstrated that BMI, body weight, waist circumference, and hip circumference were all strongly correlated with circulating leptin concentrations in this population (r > 0.56, P < 0.001 in all cases). Waist/hip ratio, triacylglycerols, insulin, glucose, and cholesterol were also associated with leptin (P < 0.05), but there was no association between leptin and age, height, or blood pressure. When these associations were adjusted for BMI, age, glucose, and waist circumference were significantly associated with leptin. The lifestyle factors examined did not help to explain the observed variation in leptin concentrations between individuals when results were adjusted for degree of adiposity and age.

New Approaches to Gene Discovery with Animal Models of Obesity and Diabetes

Abstract: DNA‐based approaches to the discovery of genes contributing to the development of type 2 diabetes have not been very successful despite substantial investments of time and money. The multiple gene‐gene and gene‐environment interactions that influence the development of type 2 diabetes mean that DNA approaches are not the ideal tool for defining the etiology of this complex disease. Gene expression‐based technologies may prove to be a more rewarding strategy to identify diabetes candidate genes. There are a number of RNA‐based technologies available to identify genes that are differentially expressed in various tissues in type 2 diabetes. These include differential display polymerase chain reaction (ddPCR), suppression subtractive hybridization (SSH), and cDNA microarrays. The power of new technologies to detect differential gene expression is ideally suited to studies utilizing appropriate animal models of human disease. We have shown that the gene expression approach, in combination with an excellent animal model such as the Israeli sand rat (Psammomys obesus), can provide novel genes and pathways that may be important in the disease process and provide novel therapeutic approaches. This paper will describe a new gene discovery, beacon, a novel gene linked with energy intake. As the functional characterization of novel genes discovered in our laboratory using this approach continues, it is anticipated that we will soon be able to compile a definitive list of genes that are important in the development of obesity and type 2 diabetes.

Leptin and the treatment of obesity

The cloning of the ob gene and subsequent discovery of the weight‐reducing protein leptin has revitalized research into body weight regulation and raised the possibility of effective pharmaceutical control of the energy balance. Leptin is secreted from adipocytes in proportion to fat mass in both humans and rodents, and circulating leptin is thought to act on the hypothalamus to inhibit feeding and stimulate energy expenditure. Hyperleptinemia appears to accompany human obesity, suggesting the development of resistance to leptin’s anorexigenic actions, although it was hoped that this resistance could be overcome by administration of exogenous leptin. Results from clinical trials suggest that the response to leptin administration is variable, and while this may be an effective treatment for obesity in some individuals, it is unlikely to be a universal treatment for the disease. Current research has now turned to examining the factors involved in potentiating leptin’s effects in the brain and the search for leptin analogs or neuropeptides involved in regulating the leptin pathway is under way in earnest, as these may yet prove to be the key to effective treatment for human obesity. Drug Dev. Res. 51:66–79, 2000.

Beacon: A novel gene involved in the regulation of energy balance

The hypothalamus plays a major role in the control of energy balance via the coordination of several neuropeptides and their receptors. We used a unique polygenic animal model of obesity, Psammomys obesus, and performed differential display polymerase chain reaction on hypothalamic mRNA samples to identify novel genes involved in obesity. In this study, we describe a novel gene that encodes a small protein we have termed beacon. Beacon mRNA gene expression in the hypothalamus was positively correlated with percentage of body fat. Intracerebroventricular infusion of beacon resulted in a dose-dependent increase in food intake and body weight and an increase in hypothalamic expression of neuropeptide Y (NPY). Simultaneous infusion of beacon and NPY significantly potentiated the orexigenic response and resulted in rapid body weight gain. These data suggest a role for beacon in the regulation of energy balance and body weight homeostasis that may be mediated, at least in part, through the NPY pathway.