Leptin Affects Pancreatic Endocrine Functions through the Sympathetic Nervous System¹

Abstract

The effects of leptin on the secretion of insulin and glucagon were examined. In an experiment involving insulin response to an iv glucose load in vagotomized rats, the plasma concentrations of insulin were significantly lower in the leptin (20 nmol/kg BW)-treated group than in a control group. However, in intact rats and rats that had undergone both vagotomy and chemical sympathectomy, this suppressive effect of leptin on insulin secretion was not detected. In an experiment involving a hypoglycemia-induced glucagon secretion test in intact rats, an iv injection of leptin (20 nmol/kg BW) augmented the plasma glucagon response to hypoglycemia. In the case of sympathectomized rats, however, this stimulative effect of leptin on glucagon secretion was not detected. In an experiment with perfused rat pancreas, the addition of leptin (20 nM) to the perfusate slightly suppressed insulin secretion, but had no effect on basal or glucopeniainduced glucagon secretion. In intact rats infused with leptin (0.31 mol/day), the expression of uncoupling protein-1 messenger RNA in interscapular brown adipose tissue was increased, whereas no such effect of leptin on the uncoupling protein-1 messenger RNA expression was observed in brown adipose tissue in chemically sympathectomized rats. These findings suggest that leptin might indirectly affect pancreatic endocrine functions, probably through its stimulative effects on the sympathetic nervous system. (Endocrinology 139: [3863][3864][3865][3866][3867][3868][3869][3870] 1998) L EPTIN, the product of the obese (ob) gene, is a 16-kDa protein that is primarily produced by adipocytes (1). A recessive mutation in the ob gene causes severe hereditary obesity in the ob/ob mouse (2), and the administration of exogenous leptin reverses this obesity (3). As a result, leptin is generally thought to be involved in the control of body weight via the regulation of energy homeostasis. Other well characterized inherited obesity mutations in the mouse and rat are diabetes (db) (4) and fatty (fa) (5), which are mutations in the leptin receptor (OB-R) genes (6 -9).Several alternate spliced isoforms (a-e, as well as others) of the OB-R have been cloned, and all of these, except for the OB-Re (soluble form), contain a single transmembrane domain (6 -9). Among them, the OB-Rb has the greatest capacity to perform signal transduction. Several lines of evidence suggest that the central nervous system, in particular the hypothalamus, is a direct target of leptin. The OB-Rb is highly expressed in those hypothalamic nuclei that are known to control the regulation of food intake and body weight (10, 11). The activity of the STAT3 transcription factor and fos gene expression are increased in the hypothalamus within 1 h after a single iv injection of leptin (12). Finally, the much higher potency in inducing weight loss of intracerebroventricular infusion of leptin than sc leptin (13) and the identification of leptin in cerebrospinal fluid are consistent with the idea that the main site of its action is...

Central Leptin Regulates the UCP1 and obGenes in Brown and White Adipose Tissue via Different β-Adrenoceptor Subtypes

“…The initial evidence came from a study showing that leptin increased norepinephrine turnover in BAT (12), and was followed by studies mapping the neural pathways within the sympathetic nervous system activated by leptin (13)(14)(15). Subsequent studies have shown that surgical (16), chemical (17,39), or genetic (18) sympathectomy blocked leptin's effects on gene expression in both BAT and WAT. The latter studies established a requirement for the long form of the leptin receptor (Ob-Rb), but did not distinguish between central versus peripheral sites of action for leptin.…”

“…It should be noted, however, that although supraphysiologic levels of leptin are capable of producing significant direct effects on adipose tissue (10,11), increments of plasma leptin in the physiological range are thought to act primarily through receptors in the hypothalamus (10). Occupancy of hypothalamic leptin receptors promotes activation of the sympathetic nervous system (12)(13)(14)(15), and recent studies using surgical (16), chemical (17), and transgenic approaches (18) have shown that norepinephrine is required for leptin effects on gene expression in both brown and white adipose tissue (19 -22). Thus, several lines of evidence support an emerging consensus that norepinephrine represents the peripheral signal linking hypothalamic leptin receptors to leptindependent changes in adipocyte gene expression.…”

Physiology of energy homeostasis: Models, actors, challenges and the glucoadipostatic loop

“…Leptin leads to increased FFA release from WAT possibly via a direct action on adipocytes [69] but much more importantly by increasing SNS activity [170,214] in the ARC [215]. This increased adipocyte lipolysis is also mediated by its direct [216] and SNS-induced [217] inhibitory effect on insulin secretion, demonstrated with changes in physiological concentrations [218].…”

Neuro-Hormonal Regulation of Immune and Metabolic Function

“…Although many of the effects of leptin on the regulation of total body fat are due to the effects of this hormone on food intake, an increasing number of studies suggest that the actions of leptin on energy balance are due, at least in part, to activation of the sympathetic nervous system (SNS) and subsequent increases in metabolism [46,47]. Furthermore, stimulation of the leptin system increases sympathetic activity in a variety of peripheral tissues [47].…”