Increased body fat mass and suppression of circulating leptin levels in response to hypersecretion of epinephrine in phenylethanolamine-N-methyltransferase (PNMT)-overexpressing mice

Epinephrine is a major stress hormone that plays a central role in the cont rol of metabolic function and energy homeostasis. To evaluate the role of e pinephrine and the physiological and pathophysiological consequences of sus tained elevation of epinephrine on metabolic and endocrine function, we stu died several metabolic parameters and circulating leptin levels in a newly developed transgenic mouse model of phenylethanolamine-N-methyltransferase (PNMT) overexpression. A 100-fold overexpression of PNMT and subsequent ele vation of epinephrine levels resulted in a marked suppression of circulatin g leptin levels in the transgenic animals (1.14 +/- 0.05 vs. 2.17 +/- 0.35 ng/ml; P < 0.01), which correlated negatively with plasma epinephrine (r = -0.82; P ( 0.05), thus providing evidence for an inhibitory action of epine phrine on leptin production in vivo. In parallel, we found a marked increas e in the body fat content of the transgenic animals (12.54 +/- 1.5 vs. 6.22 +/- 0.2%; P < 0.01) that was accompanied by enlarged adipocytes, indicatin g an increased lipid storage in PNMT transgenic mice. Interestingly, howeve r, transgenic animals had normal body weight and did not exhibit major alte rations in carbohydrate metabolism, as evidenced by analysis of random and fasted blood glucose levels, plasma insulin and C peptide levels, and insul in tolerance test. The metabolic alterations observed were not secondary to changes in food intake or increased activity of the hypothalamic-pituitary -adrenal axis, as there were no differences in these parameters. In summary , sustained primary overproduction of epinephrine resulted in suppression o f plasma leptin levels and increased lipid storage in the PNMT transgenic m ice. The concerted action of the sympathoadrenal system and reduced leptin may contribute to defending energy reservoirs while maintaining a normal bo dy weight, which may be of vital importance under conditions of stress and energy deficiency.