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Background and Aims: Hypothalamus and white adipose tissue interact towards energy homeostasis. Leptin is secreted from white adipose tissue and modulates the expression of appetite-regulating hypothalamic neuropeptides. Among them, MCH, an orexigenic neuropeptide, is negatively regulated by leptin. Our group has identified white adipose tissue, the major source of circulating leptin, as a peripheral target of MCH. Adipocytes bear functional MCH receptors (MCHR1), the activation of which stimulates leptin synthesis and secretion. However, very few studies have addressed the physiological regulators of MCHR1 in white adipose tissue. Thus in the present study we examined in mice the effects of fasting, diet-induced obesity (DIO) and activation of the sympathetic nervous system on MCHR1 expression in fat. Methods: We studied different mouse models (n=6-12/group) with endogenous or experimentally altered serum leptin levels. Another cohort of mice was treated with a selective beta3 adrenergic receptor agonist (CL 316.243; 1mg/kg ip). This receptor is mainly located in fat and regulates lipolysis and thermogenesis. MCHR1 expression in white adipose tissue was measured by real time RT-PCR using RNA isolated from epididymal fat pads. Results: Fasting, which results to a significant drop in serum leptin levels, was associated with a 2.2-fold upregulation of MCHR1 mRNA. This was reversed in fasted animals receiving leptin replacement treatment. Mice fed a western type of diet for 6 weeks became obese and hyperleptinemic. DIO mice had significantly lower MCHR1 levels in their white adipose tissue, compared to littermates fed a standard chow. Whether fed standard chow or a western type diet, mice treated with a beta3 agonist for 24hrs became anorexic and lost weight. However, despite low serum leptin in this model, sympathetic activation of the adipose tissue was associated with a significant, 5-fold downregulation of MCHR1 expression. Conclusion: Leptin and sympathetic nervous system activation negatively and independently regulate MCHR1 expression in white adipose tissue. The effect of leptin on MCHR1 expression in fat in conjunction with the previously established stimulatory effect of MCH on leptin synthesis and secretion suggest the existence of a feedback loop for MCH action in adipocytes.