Regulation of Expression of ob mRNA and Protein by Glucocorticoids and cAMP

Abstract

Regulation of obese gene (ob) expression in ob/ob and db/db mice and in cultured rat adipocytes was examined. It has been demonstrated that exogenous human OB protein (leptin) treatment reduces food intake and weight gain, as well as insulin, glucose, and corticosterone levels in ob/ob mice. In the present report we show that leptin treatment down-regulates endogenous adipose ob mRNA. However, treatment of isolated rat adipocytes with 100 ng/ml human or murine leptin had no direct effect on expression of endogenous ob mRNA, suggesting that leptin may be able to down-regulate its own expression by an indirect, non-autocrine mechanism. Glucocorticoids increased both ob mRNA levels and secreted leptin levels in vitro. Conversely, agents that increase intracellular cAMP, such as ␤-adrenergic agonists or Bt 2 cAMP itself, decreased ob mRNA expression and leptin secretion. Therefore, increased glucocorticoid levels and decreased sympathetic neural activity may contribute to the elevated ob mRNA expression observed in genetically obese, hyperglucocorticoid rodents. Furthermore, leptin might regulate its own expression through a feedback mechanism involving the hypothalamic pituitary axis.

Effects of three weeks of mild sleep restriction implemented in the home environment on multiple metabolic and endocrine markers in healthy young men

“…Interestingly in the present study, reduction of leptin was observed only in the third week of sleep reduction and coincided with an increase in bodyweight, which initially appears counterintuitive but corresponds well to what is found in cohort studies (reviewed by [40]). Leptin expression may be inhibited directly by catecholamines [41] . The effects of lowered levels 10 of leptin on hypothalamic centres regulating appetite, would potentially lead to increased food intake and weight gain.…”

Regulation of adipocytokines and insulin resistance

“…TZDs consistently suppress leptin expression in rodent fat in vivo and in vitro (Table 1) [113,114,115,116]. Furthermore, β-adrenergic activation rapidly decreases leptin expression and secretion in primary adipocytes in vitro and mice in vivo (Table 1) [117,118]. Insulin is a potent activator of leptin mRNA expression and protein secretion [49] and it is plausible that insulin is the major mediator of increased post-prandial leptin concentrations (Table 1) [119,120,121].…”

“…Insulin is a potent activator of leptin mRNA expression and protein secretion [49] and it is plausible that insulin is the major mediator of increased post-prandial leptin concentrations (Table 1) [119,120,121]. Furthermore, glucocorticoids stimulate leptin expression and secretion in vivo and in vitro (Table 1) [49,118,122]. Of interest, this increase in leptin synthesis can be reversed by TZD treatment in humans [123].…”

Clinical implications of leptin and its potential humoral regulators in long-term low-calorie diet therapy for obese humans

“…In rodents, it has been reported that sympathetic activation, cAMP and b-receptor agonist down-regulate leptin gene expression and lower the plasma leptin level accompanied by an increase in lipolysis (Auwerx & Staels, 1998;Slieker et al, 1996;Mantzoros et al, 1996). In vitro studies demonstrated that NEFA inhibits leptin gene transcription in 3T3-L1 adipocytes (Rentsch & Chiesi, 1996), and that elevated intracellular NEFA induced by acyl-CoA synthase inhibitor down-regulates leptin synthesis and secretion in primary cultured rat adipocytes (Shintani et al, 2000).…”

“…These observations strongly indicate the presence of leptin resistance in human obesity Heek et al, 1997;Arch et al, 1998;Beaufrere & Morio, 2000). In addition to the regulation associated with adipose tissue mass, leptin production is known to be regulated by such factors as peripheral nutritional status (Kolaczynski et al, 1996a,b;Boden et al, 1996;Reseland et al, 2001), sympathetic nerve activity (Auwerx & Staels, 1998;Slieker et al, 1996;Mantzoros et al, 1996), and a series of humoral factors (Auwerx & Staels, 1998).…”