Endocrinology Vol. 139, No. 9 4016-4020
Copyright © 1998 by The Endocrine Society
A Regulatory Loop Between the Hypothalamo-Pituitary-Adrenal (HPA) Axis and Circulating Leptin: A Physiological Role of ACTH
Eduardo Spinedi and
Rolf C. Gaillard
Neuroendocrine Unit (E.S.), IMBICE, 1900 La Plata, Argentina; and
Division of Endocrinology, Diabetology and Metabolism (E.S., R.C.G.),
University Hospital, CH 1011 Lausanne, Switzerland
Address all correspondence and requests for reprints to: Eduardo Spinedi, Ph.D., IMBICE (CIC-CONICET), Calle 526 e/10 y 11, Neuroendocrine Unit, P.O. Box 403, La Plata 1900, Argentina.
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Abstract
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The product of the ob/ob gene, leptin, is known to be able to exert a
modulatory role on HPA axis function. The aim of the present study was
to determine whether endogenous ACTH and glucocorticoids exert any
regulatory effect on leptin secretion. For this purpose bilaterally
adrenalectomized (ADX) or sham operated (Sham) adult male rats were
implanted with an indwelling i.v. catheter. A subgroup of ADX animals
received, at the same time of surgery, a s.c. corticosterone (B) pellet
(75 mg) (ADX + B). All animals were subjected to experimental designs
7 days after surgery. Our results indicate, as expected, that 7-day ADX
animals have several fold increased basal ACTH plamsa levels and non
detectable circulating B, whereas ADX + B rats showed basal plasma
ACTH levels in the range of Sham values and plasma B concentrations of
about 5 µg/dl. Interestingly, basal plasma leptin levels were
significantly (P < 0.05) decreased by 7 days post ADX, and B
replacement therapy (ADX + B) restored circulating leptin to Sham
levels. Acute dexamethasone (Dxm; 30 µg/kg body weight, i.v.)
treatment induced a very rapid decrease in plasma ACTH concentrations
in both Sham and ADX rats, as well as a decrease in plasma B levels in
Sham rats. Interestingly, Dxm test had no effect on plasma leptin
levels in Sham animals; however, in ADX rats, the synthetic
glucocorticoid increased plasma leptin concentrations, restoring the
levels observed in Sham rats. This effect occurred at the same time
when plasma ACTH levels were decreasing toward basal Sham values. These
results clearly indicate that, beside the known effects of leptin on
HPA axis function, circulating ACTH and glucocorticoid are able to
modulate leptin secretion in plasma. The lack of circulating
glucocorticoid and/or increased plasma ACTH concentrations, are
responsible for decreasing leptin output, whereas decreased plasma ACTH
concentrations allow an increase of leptin secretion in blood. Our data
strongly support the existence of a closed, bi-directional, circuit
between HPA axis function and adipose tissue metabolism. They further
indicate the physiological relevance of different types of stress
associated with many phenotypes of obesity.
Received June 25, 1998.
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