Modulation of the Metabolic Effects of Leptin by the Brain Renin-Angiotensin System

Genetic deletion or delivery of antagonists of the renin-angiotensin system (RAS) directly to the brain abolishes both renal and adipose sympathetic nervous activity (SNA) responses to leptin, suggesting a cross-talk between these central cardiovascular / metabolic control systems. To further explore this mechanism of cross-talk, we examined the sensitivity of metabolic responses in mice with transgenic hyperactivity of the brain RAS (“sRA” mice) to acute leptin treatment. sRA mice, previously shown to exhibit hypertension, polydipsia, and elevated SNA and resting metabolic rate, exhibit brain-specific RAS hyperactivity through neuronal expression of human renin via the synapsin promoter and expression of human angiotensinogen via its own promoter. When housed at standard room temperature (23°C), twice-daily leptin injections (1 mg/kg, i.p., 3 hrs into light phase and 2 hrs preceding dark phase of a 12:12-hr cycle) caused significant and similar reductions in body mass (control -0.76±0.13, n=5 male; sRA -0.65±0.09 g/d, n=5 male, P=0.46) and food intake (-1.43±0.69 vs -1.99±0.27 kcal/d, P=0.63) in littermate control and sRA mice. When housed at thermoneutrality (30°C) in an OxyMax (Columbus Instruments) CLAMS apparatus, leptin injections had minimal effects on total daily food intake in control mice (from 7.4±0.6 at baseline to 8.1±0.5 kcal/d with leptin, n=4 male + 4 female, P=0.29), but reduced food intake in sRA mice (from 8.3±0.7 to 6.0±0.4 kcal/d, n=4 male + 4 female, P=0.003). sRA mice were more sensitive to leptin’s suppressive effect on physical activity (control from 998±148 to 655±90, P=0.10; sRA from 1232±304 to 588±41 counts/d, P=0.005). Unexpectedly, leptin had a suppressive effect upon metabolic rate in sRA mice (control from 16.4±1.3 to 16.8±0.9, P=0.44; sRA from 20.2±1.1 to 17.5±0.9 kcal/kg lean/hr, P<0.001). Together, these data support a cross-talk between the brain RAS and leptin signaling in the control of metabolic function. These data suggest a complex and context-dependent mechanism of interaction between leptin and brain angiotensin, with gross alterations in leptin-induced food, physical activity, and metabolic rate responses when tested in a thermoneutral environment.