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Leptin, a hormone derived from adipose tissue, regulates energy homeostasis and body weight. In the mouse, serum leptin levels, when measured by radioimmunoassay (RIA), increase by a factor of more than 50 times during pregnancy, compared with those in the non-pregnant state. It is well known that mouse placenta produces the secretory isoform of the leptin receptor, OB-Re. In order to investigate the issue of whether serum leptin levels are actually increased during pregnancy or whether the increased OB-Re concentration plays a role in this phenomenon, serum leptin levels were determined by the immunoprecipitation of leptin using anti-leptin antibody, and were found to be increased only by about ten times during pregnancy. To investigate the influence of OB-Re on leptin measurement by the RIA procedure, serum leptin levels were measured by the RIA after the addition of OB-Re to the serum. The apparent values of leptin levels increased in parallel with the amount of OB-Re added to the serum. Leptin levels, as determined by the RIA, might therefore provide artificially high values when serum levels of the secretory form of OB-R are high, in cases, for example, such as the last period of pregnancy in mice.

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...

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