Abstract: Administration of leptin affects food intake and body weight in animals and humans by a mechanism involving actions on specific regions of the hypothalamus. CIS-1, SOCS-1, SOCS-2 and SOCS-3 genes were investigated for their ability to antagonize leptin action. In mammalian cell lines, SOCS-3 completely blocked leptin induced signal- transduction, whereas CIS, SOCS-1 and SOC-2 were without effect. SOCS-3 is a major target of leptin action in leptin responsive cells in the hypothalamus, and SOCS-3 is a potent inhibitor of leptin signaling. Increased SOCS-3 activity in leptin-responsive neurons is a potential mechanism for the leptin resistance observed in syndromes of obesity, affective mood disorders and reproductive disorders.

Abstract: Deletion of the rsk2 gene in mice results in reduced body weight, reduced body fat and reduced sensitivity to diet-induced weight gain, as well as lower levels of leptin in the serum of rsk2 deficient mice and lower levels of oxygen consumption, as compared to wild type littermates. Thus, altering RSK2 activity provides a means for modulating RSK2-mediated signaling and therefore modulating the above described physiological parameters. The present invention encompasses methods and compositions for altering, or modulating in a mammal, body weight, fat content, leptin levels by altering, or modulating, RSK2 activity. Specifically encompassed in the present invention are methods and compositions to alter activity of the RSK2. The present invention is drawn to a model for the study of Coffin-Lowry syndrome as well as an in vivo model to screen and test therapeutic agents for the treatment of Coffin-Lowry syndrome.

Abstract: Methods and compositions for altering, or modulating CNTF activity by altering or modulating cytokine inhibitor activity are provided. Specifically encompassed are methods and compositions to alter activity of cytokine inhibitors such as SOCS-1, -2, and -3. SOCS-3 expression is rapidly induced by CNTF treatment in regions of the hypothalamus that are known to be involved in the regulation of body weight. As described herein, a SOCS-3-mediated CNTF cell-signaling inhibitory pathway exists, suggesting that SOCS-3 is a negative regulator of CNTF signal-transduction in the brain. Since CNTF treatment of animals suppresses appetite and induces weight loss, inhibition of SOCS-3 expression or activity is a potential target for the development of drugs aimed at improving CNTF sensitivity or prolonging CNTF activity in a mammal and inducing weight loss. Thus, altering SOCS-3 activity provides a means for modulating CNTF-induced cell signaling and therefore modulating bodyweight.