Is leptin an insulin counter‐regulatory hormone?

Abstract

Leptin, the product of the ob gene, controls appetite through the hypothalamus and may affect many other tissues because of the widespread distribution of its receptors. Leptin is synthesized by white adipose tissue (WAT) under conditions of high energy availability and insulin stimulus. Glucocorticoids enhance this synthesis and catecholamines hamper leptin production. Leptin diminishes insulin secretion by the pancreatic beta cells and induces insulin resistance. In fact leptin hampers insulin action on WAT itself in a negative feedback loop. The evidence acquired in studies on diabetics, starvation, refeeding and insulin and glucose clamps supports this interpretation, which may also explain part of the difficulties encountered by the current postulate that links leptin to WAT mass size signalling to the brain. Leptin may be, essentially, a counter-regulatory hormone limiting the insulin drive to store energy in the form of fat, its effects reaching from a decrease in food intake to lower insulin secretion and increased resistance to insulin and lower glucose uptake and fat synthesis by WAT.Key words: Leptin; Insulin; Obesity Leptin expression in white adipose tissueThe study of the mechanisms controlling body weight has received an enormous boost during the last year thanks to the identification of the ob gene and its product, leptin, which induces the loss of fat in ob/ob mice [1][2][3]. Leptin is expressed only in adipose tissues [4], though it is more intensely expressed in white than in brown adipose tissue [5].The gene db, encoding the leptin receptor has been characterized in mice [6], and in rats, where it has been found to coincide with the fa mutation [7]; its defect results in the overexpression of the ob gene [8]. Leptin down-regulates the expression of the ob gene via paracrine or endocrine pathways, since isolated adipocytes do not respond to direct leptin stimulation [9]. Sympathetic activity or cAMP lowers the expression of the ob gene [9]. In white adipose tissue, ß-adrenergic stimulation decreases ob gene expression [5]. Cold exposure, directly related to sympathetic stimulation rewarming, also lowers the synthesis of leptin in adipose tissue, an effect that can be partially reversed by reheating [10].In vivo leptin release by adipose tissue has been demonstrated in humans and circulating leptin levels are correlated with degree of obesity [11], because of overexpression of the ob gene [12]. Leptin and insulin levels, as well as body weight, are inter-correlated [13]. However, non-insulin-dependent *Corresponding author. Fax: (34) (3) 4021559. E-mail: remesar@porthos.bio.ub.es diabetics show leptin levels which do not differ from those of non-diabetic humans of the same body mass index [14].In normal rats, ob gene expression is down-regulated by insulinemia under euglycemic conditions [15]. The presence of insulin is also required for leptin release [16]. In streptozotocin-diabetic rodents, however, the low levels of ob gene mRNA are not fully restored with continuous insulin treatm...

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