Cardiovascular and sympathetic effects of disrupting tyrosine 985 of the leptin receptor.
Leptin acts in the brain to regulate food intake and energy expenditure. Leptin also increases renal sympathetic nerve activity and arterial pressure. The divergent signaling capacities of the leptin receptor (ObRb) mediate the stimulation of various intracellular pathways that are important for leptin control of physiological processes. We evaluated the cardiovascular and sympathetic consequences of disrupting the signal emanating from tyrosine985 of ObRb. For this, we used Lepr(L985) (l/l) mice, which carry a loss of function mutation replacing tyrosine985 of ObRb with leucine. Body weight of l/l mice was not significantly different from wild-type controls. In contrast, radiotelemetry measurements revealed that the l/l mice had higher arterial pressure and heart rate as compared with controls. Ganglionic blockade caused a greater arterial pressure fall in the l/l mice relative to controls. In addition, leptin treatment induced a larger increase in arterial pressure and heart rate in the l/l versus wild-type mice. Finally, we compared the response of renal and brown adipose tissue sympathetic nerve activity to intracerebroventricular injection of leptin (2 μg) between l/l and control mice. Leptin-induced increase in renal sympathetic nerve activity was greater in l/l mice relative to controls. In contrast, the brown adipose tissue sympathetic nerve activity response to leptin was attenuated in the l/l mice relative to controls. These data indicate that selective loss of leptin receptor signaling emanating from tyrosine985 enhances the cardiovascular and renal sympathetic effects of leptin. These findings provide important insight into the molecular mechanisms underlying leptin's effects on the sympathetic cardiovascular function and arterial pressure.
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Shannon M
SM
Harlan
Donald A
DA
Morgan
David J
DJ
Dellsperger
Martin G
MG
Myers
Allyn L
AL
Mark
Kamal
K
Rahmouni
D002001:Adipose Tissue, Brown / Q000294:innervation / Q000378:metabolism; D019943:Amino Acid Substitution; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics*; D007668:Kidney / Q000294:innervation / Q000378:metabolism; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
D020738:Leptin; D054411:Receptors, Leptin
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