(Scanned from the Applicant's Description): With one out of every two adult Americans rated as medically obese, obesity is the number one health problem in the United States. Since it is a major risk factor for heart disease, diabetes, stroke, hypertension, and morbidity, the treatment of obesity and associated diseases entails enormous medical costs. The major objective of this proposal is (1) to examine whether viral vector mediated delivery of weight-reducing signals, such as leptin, is a viable therapy (gene therapy), alternative to the pharmacologic approach, to control body weight (BW) gain for extended periods in normal male and female rats and in rodents with obesity due to environmental (diet-induced) and genetic factors. We believe that leptin acts by (1) augmenting energy expenditure (thermogenesis) and/or curbing appetite and (2) that the beneficial effects of leptin gene therapy are manifest at sites that enhance energy expenditure and modify hypothalamic appetite regulating signals such as the orexigenic signals, NPY, AgrP and GABA, and the anorexigenic melanocortin signal alpha-MSH, and intracellular signal transduction sequalae involving STAT3 and SOCS-3. We have successfully generated a recombinant adeno-associated virus (rAAV) vector to efficiently transfer the naturally occurring body weight reducing peptide, leptin (rAAV-lep).
Aim 1 : Examine the long-term (one-year) efficacy of rAAV-lep to reduce BW gain when delivered intracerebroventricular (icv) or systemically in out-bred Sprague-Dawley (SD) rats and obese rats maintained on a high-energy (HE) diet.
Aim 2 : Evaluate the efficacy of icv and peripheral rAAV-lep in those genetic models of obesity that (1) lack leptin (ob/ob mice) and (2) display resistance to peripheral and not central leptin (New Zealand obese mice); and (3) lack NPY (-/-) and display obesity when maintained on HE diet. Finally, we will also characterize the underlying mechanism(s) if excessive ectopic leptin itself induces leptin ineffectiveness (resistance) in these experiments. The causal mechanisms responsible for phenotype changes will be identified by evaluation of hypothalamic leptin expression and signaling through analysis of gene expression, and peptide levels, signal transduction sequalae (p-STAT3 and SOCS-3) and metabolic indices (body temperature, 24h urinary NE activity, oxygen consumption, UCP1 mRNA, and blood leptin, insulin glucose, and corticosterone levels). The outcome of these investigations will provide fundamental information on the broader potential of using gene delivery of naturally occurring anorectic molecules for BW control and their mechanism of action. This new knowledge will be applied to the ultimate goal of site-directed gene delivery aimed at the newly identified vulnerable loci in hypothalamic signaling to curb overeating and abnormal weight gain.
|Turner, Russell T; Kalra, Satya P; Wong, Carmen P et al. (2013) Peripheral leptin regulates bone formation. J Bone Miner Res 28:22-34|
|Iwaniec, Urszula T; Boghossian, Stéphane; Trevisiol, Cynthia H et al. (2011) Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats. J Bone Miner Res 26:1506-16|
|Kalra, S P (2011) Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention? Gene Ther 18:319-25|
|Jackson, M A; Iwaniec, U T; Turner, R T et al. (2011) Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats. Peptides 32:1575-80|
|Kalra, Satya P; Kalra, Pushpa S (2010) Neuroendocrine control of energy homeostasis: update on new insights. Prog Brain Res 181:17-33|
|Kalra, Satya P; Dube, Michael G; Iwaniec, Urszula T (2009) Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides 30:967-73|
|Kojima, Shinya; Asakawa, Akihiro; Amitani, Haruka et al. (2009) Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides 30:962-6|
|Kalra, Satya P (2009) Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation. Peptides 30:1957-63|
|Iwaniec, U T; Dube, M G; Boghossian, S et al. (2009) Body mass influences cortical bone mass independent of leptin signaling. Bone 44:404-12|
|Kalra, Satya P (2008) Disruption in the leptin-NPY link underlies the pandemic of diabetes and metabolic syndrome: new therapeutic approaches. Nutrition 24:820-6|
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