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Increased Body Fat Mass and Suppression of Circulating Leptin Levels in Response to Hypersecretion of Epinephrine in Phenylethanolamine-N-Methyltransferase (PNMT)-Overexpressing Mice¹

Department of Internal Medicine III, University of Leipzig (A.B., A.H.), 04103 Leipzig, Germany; Intramural Research Program, National Institute of Neurological Disorders and Stroke (G.E.), National Institute of Diabetes and Digestive and Kidney Diseases (A.L.C.), and National Institute of Child Health and Human Development (G.P.C., S.R.B.), National Institutes of Health, Bethesda, Maryland 20892; Pipeline Biotech A/S (K.K.), Silkeborg, Denmark; Diabetes Research Institute (W.A.S.), Düsseldorf 40225, Germany; and Children’s Hospital, University of Erlangen-Nürnberg (H.S.), Erlangen 91054, Germany

Address all correspondence and requests for reprints to: Dr. Antje Böttner, Department of Internal Medicine III, University of Leipzig, Ph. Rosenthal Strasse 27, 04103 Leipzig, Germany. E-mail: antje.boettner{at}gmx.net

Epinephrine is a major stress hormone that plays a central role in the control of metabolic function and energy homeostasis. To evaluate the role of epinephrine and the physiological and pathophysiological consequences of sustained elevation of epinephrine on metabolic and endocrine function, we studied 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 elevation of epinephrine levels resulted in a marked suppression of circulating 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 epinephrine on leptin production in vivo. In parallel, we found a marked increase 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, indicating an increased lipid storage in PNMT transgenic mice. Interestingly, however, transgenic animals had normal body weight and did not exhibit major alterations in carbohydrate metabolism, as evidenced by analysis of random and fasted blood glucose levels, plasma insulin and C peptide levels, and insulin 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 of plasma leptin levels and increased lipid storage in the PNMT transgenic mice. The concerted action of the sympathoadrenal system and reduced leptin may contribute to defending energy reservoirs while maintaining a normal body weight, which may be of vital importance under conditions of stress and energy deficiency.

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