title: Partial leptin restoration increases hypothalamic-pituitary-adrenal activity while diminishing weight loss and hyperphagia in streptozotocin diabetic rats.
abstract: Chronic leptin administration at pharmacologic doses normalizes food intake and body weight in streptozotocin (STZ)-diabetic rats. We examined the metabolic effects of acute partial physiological leptin restoration in STZ-diabetic rats by using subcutaneous osmotic mini pumps. Groups: (1) Rats infused with vehicle (DV); (2) rats infused with recombinant murine methionine leptin (DL) at 4.5 microg . (kg body weight . d)(-1); (3)pair-fed rats (DP) given a food ration matching that consumed by the DL group. A fourth group of nondiabetic, normal (N) rats was also studied to assess normal metabolic efficiency, hypothalamic-pituitary-adrenal (HPA) activity and sympathoadrenal activity. Following leptin infusion, food consumption by DL rats was significantly lower than in DV rats. Paradoxically, despite a similar food intake to that of the DP group, which demonstrated a 40% reduction in body mass, DL rats increased their initial body weight by approximately 20% (P < .05). Plasma corticosterone and ACTH concentrations were elevated by 2-fold to 3-fold in DL versus N, DP, and DV rats. In the pars distalis, glucocorticoid receptor (GR) mRNA levels were significantly higher in DL and DP rats compared with N and DV rats. Our results suggest that partial restoration of physiologic leptin: (1) successfully reduces hyperphagia while allowing body weight gain in STZ-diabetic rats; (2) increases corticosterone levels in STZ-diabetic rats, which may in turn counteract the anorexic effects of diabetes; and (3) is associated with increased pituitary GR mRNA levels, despite elevated corticosterone levels, suggesting that leptin may interfere with the negative feedback regulation of the HPA axis.
authors.affiliation: Department of Physiology, University of Toronto, Ontraio, Canada.
authors.forename: Eitan M
authors.initials: EM
authors.lastname: Akirav
authors.forename: Owen
authors.initials: O
authors.lastname: Chan
authors.forename: Karen
authors.initials: K
authors.lastname: Inouye
authors.forename: Michael C
authors.initials: MC
authors.lastname: Riddell
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
authors.forename: Mladen
authors.initials: M
authors.lastname: Vranic
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D004837:Epinephrine / Q000097:blood; D006963:Hyperphagia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000097:blood; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D009638:Norepinephrine; D004837:Epinephrine