Low plasma leptin levels contribute to diabetic hyperphagia in rats.

Abstract

The adipocyte hormone leptin reduces food intake in normal animals. During uncontrolled type 1 diabetes, plasma leptin levels fall, whereas food intake increases. To test the hypothesis that low leptin levels contribute to diabetic hyperphagia, we investigated the e ffect on food intake of replacement of leptin at basal plasma concentrations for 7 days in Long-Evans rats with uncontrolled diabetes induced by streptozotocin (STZ). One group of STZ diabetic rats received saline (STZ + Sal) (n = 11), while the other group (STZ + Lep) (n = 15) received a subcutaneous infusion of recombinant rat leptin (100 µg ؒ k g -1 ؒ d a y -1 ) via osmotic minipumps. A nondiabetic control group (Con) (n = 11) received saline only. In the STZ + Sal group, plasma leptin levels decreased by 75% (P < 0.05) from 2.4 ± 0.5 on the day before STZ/citrate buffer vehicle ( Veh) injection (day 0) to 0.6 ± 0.2 ng/ml on day 7. In contrast, plasma leptin levels on days 3-7 were comparable to pretreatment values in both the STZ + Lep group (day 0: 2.6 ± 0.4 vs. day 7: 2.5 ± 0.3 ng/ml, NS) and the Con group (day 0: 3.8 ± 0.4 vs. day 7: 2.9 ± 1.0 ng/ml, NS). In the STZ + Sal group, daily food intake increased gradually to values 43% above basal by day 7 (day 0: 24 ± 2 to day 7: 33 ± 3 g, P < 0.05), whereas food intake did not increase in either the STZ + Lep group (day 0: 24 ± 1 vs. day 7: 21 ± 2 g, NS), or the Con group (day 0: 23 ± 1 vs. day 7: 23 ± 2 g). Plasma glucose levels exceeded nondiabetic control values (7.7 ± 0.2 mmol/l) in both diabetic groups, but were lower in the STZ + Lep group (17.2 ± 1.8 mmol/l) than in the STZ + Sal group (24.3 ± 1.1 mmol/l, P < 0.05). To determine if sensitivity to leptin-induced anorexia was affected by STZ treatment, a second experiment was performed in which the effect of intracerebroventricular leptin injection (at doses of 0.35, 1.0, or 3.5 µg) on food intake was measured 10 days after STZ or Veh treatment. Leptin suppressed both 4-and 24-h food intake in the two groups to an equal extent at every dose (by 15, 22, and 35%, respectively). These findings support the hypothesis that the effect of uncontrolled diabetes to lower leptin levels contributes to diabetic hyperphagia and that this effect is not due to altered leptin sensitivity. T he hypothesis that body fat stores are subject to homeostatic regulation proposes that humoral signals generated in proportion to adiposity act in the central nervous system (CNS) to reduce food intake and body weight (1,2). Insulin, secreted from the pancreatic ␤-cells, and leptin (3), secreted from adipocytes, are both implicated in this homeostatic control system. Both hormones are secreted in proportion to body fat stores (4,5) and recent energy intake (6-8), and receptors for both insulin and leptin are concentrated in hypothalamic areas that control food intake and energy expenditure (9,10). Moreover, administration of either hormone into the brain (11-14) causes sustained reductions of food intake and body weight, whereas both insulin deficiency (as occurs in uncon...

Hepatic Expression of a Targeting Subunit of Protein Phosphatase-1 in Streptozotocin-diabetic Rats Reverses Hyperglycemia and Hyperphagia Despite Depressed Glucokinase Expression

“…In fact, within a subset of several AdCMV-G M ⌬C (n ϭ 4) or control (n ϭ 3) STZ-treated-animals with no significant differences in their plasma leptin levels (0.70 Ϯ 0.15 versus 0.74 Ϯ 0.01 ng/ml in G M ⌬C-expressing versus control animals, respectively), food intake was still dramatically reduced in the G M ⌬C-expressing animals relative to controls (86 Ϯ 4.8 versus 126 Ϯ 2.5 mg/g/ day, respectively). Furthermore, work from another laboratory shows that STZ treatment does not influence leptin sensitivity in rats (17). In sum, whereas we consider it unlikely that leptin makes a significant contribution to the complete normalization of food intake in the STZ-injected, AdCMV-G M ⌬C-treated rats, some contribution of the hormone cannot be rigorously excluded at the present time.…”

“…This is clearly not the only mechanism at work, however, based on a study by others of the effects of leptin infusion in STZ-induced diabetic rats (17). In these studies, infusion of leptin at a rate that allowed circulating levels of the hormone to be restored to those found in non-STZ-injected controls resulted in complete normalization of food intake.…”

Metabolic decompensation in children with type 1 diabetes mellitus associated with increased serum levels of the soluble leptin receptor

“…Thus, we hypothesize that this molar excess of sOB-R contributes to leptin insensitivity, which may support substrate uptake and a decrease of energy consumption in a catabolic state like newly diagnosed T1DM. Hyperphagia observed prior to, or shortly after, starting insulin substitution could be partly explained by the distinctive changes of the leptin axis (31,32). Moreover, upregulation of the soluble leptin receptor appears to be a common mechanism to compensate substrate deficiency in energy deprivation states.…”

Leptina: o diálogo entre adipócitos e neurônios

“…Postula-se também que a leptina isoladamente esteja associada com a hiperfagia vista em casos descompensados de diabetes tipo 1 (DM1). Isto porque a hiperfagia diabética foi abolida após administração da leptina em modelos murinos de DM1 (50). Um dos aspectos que ainda fascina os pesquisadores é saber porque os efeitos da leptina sobre a redução do peso se dão preferencialmente às custas da diminuição exclusiva de tecido adiposo (51).…”