LEPTIN INHIBITION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN RESPONSE TO STRESS

Leptin is a newly identified protein hormone that is synthesized and s ecreted by adipose tissue. Absence of the mature hormone is responsibl e for the obese phenotype of ob lob mice. The hypothalamic-pituitary-a drenal axis (HPAA) is activated in ob lob mice, and chronic administra tion of leptin to ob/ob mice decreases plasma corticosterone levels, s uggesting that the adipose hormone is capable of inhibiting the HPAA. The aim of this study was to determine whether leptin feeds back acute ly to inhibit the HPAA of normal mice and rats. Male C57BL mice were i njected ip with 100 mu l saline and 2 or 4 mu g/g BW mouse leptin in s aline vehicle, and 4 h later they were subjected to 2 h of restraint s tress by taping the hind limbs together or no stress. Kind leg restrai nt stimulated the HPAA as measured by significant (P < 0.05) elevation of both ACTH and corticosterone. Pretreatment with recombinant mouse leptin blocked the stress-mediated stimulation of both plasma hormones . To determine whether this inhibition was exerted at the hypothalamic level through inhibition of CRH, we studied leptin action on isolated rat hypothalami perifused with Krebs-Ringer buffer containing glucose (5.5 mM). CRH secretion was stimulated by decreasing the glucose conc entration of the buffer to 1.1 mM. A surge of CRH was released over a 2-h period (basal integrated release was 14.4 +/- 1.6 pg/2 h, n = 5 an d increased to 34.7 +/- 3.1 pg/2 h, n = 14). This response was blacked by mouse leptin in a dose-dependent manner (integrated stimulated CRH secretion was 30.6 +/- 2.5 pg/2 h, n = 5; 20.5 +/- 3.6 pg/2 h, n = 7; 15.3 +/- 4.3 pg/2 h, n = 3 for 1 nM, 3 nM and 30 nM, respectively). L eptin did not alter secretion of ACTH from rat primary cultured pituit ary cells. These data demonstrate that leptin can inhibit hypothalamic CRH release, either directly or indirectly through another hypothalam ic neuropeptide such as neuropeptide-Y. Dysfunctional leptin, insuffic ient leptin levels, or leptin resistance should each result in a parti al open loop, thereby accounting for elevated glucocorticoid levels th at accompany and contribute to many obese phenotypes. Leptin's ability to inhibit CRH release is the likely explanation for its ability to i nhibit activation of the HPAA in response to stress.