Involvement of Hypothalamic AMP-Activated Protein Kinase in Leptin-Induced Sympathetic Nerve Activation

In mammals, leptin released from the white adipose tissue acts on the central nervous system to control feeding behavior, cardiovascular function, and energy metabolism. Central leptin activates sympathetic nerves that innervate the kidney, adipose tissue, and some abdominal organs in rats. AMP-activated protein kinase (AMPK) is essential in the intracellular signaling pathway involving the activation of leptin receptors (ObRb). We investigated the potential of AMPK alpha 2 in the sympathetic effects of leptin using in vivo siRNA injection to knockdown AMPK alpha 2 in rats, to produce reduced hypothalamic AMPK alpha 2 expression. Leptin effects on body weight, food intake, and blood FFA levels were eliminated in AMPK alpha 2 siRNA-treated rats. Leptin-evoked enhancements of the sympathetic nerve outflows to the kidney, brown and white adipose tissues were attenuated in AMPK alpha 2 siRNA-treated rats. To check whether AMPK alpha 2 was specific to sympathetic changes induced by leptin, we examined the effects of injecting MT-II, a melanocortin-3 and -4 receptor agonist, on the sympathetic nerve outflows to the kidney and adipose tissue. MT-II-induced sympatho-excitation in the kidney was unchanged in AMPK alpha 2 siRNA-treated rats. However, responses of neural activities involving adipose tissue to MT-II were attenuated in AMPK alpha 2 siRNA-treated rats. These results suggest that hypothalamic AMPK alpha 2 is involved not only in appetite and body weight regulation but also in the regulation of sympathetic nerve discharges to the kidney and adipose tissue. Thus, AMPK might function not only as an energy sensor, but as a key molecule in the cardiovascular, thermogenic, and lipolytic effects of leptin through the sympathetic nervous system.