Rats with hypothalamic obesity are insensitive to central leptin injections

Genetically determined obesities, involving leptin- and melanocortin-signal ing pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four m edial cell groups contain leptin receptors. To determine which of these cel l groups normally mediates the effects of leptin on food intake and body we ight gain, we injected colchicine bilaterally into each nucleus and determi ned the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in shamlesioned rats decreased food intake during the dark period, b ut not during the light period. Lesions of the arcuate (ARC), paraventricul ar (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivit y; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivi ty to leptin on feeding and body weight gain. Although rats with ARC and PV N lesions were obese, they were still capable of reducing caloric efficienc y over the 5 days of study and increasing uncoupling protein content in int erscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathw ays. We conclude that the medial hypothalamic cell groups, each with a diff erent role in energy balance, are all necessary for normal leptin responsiv eness.