Relation between leptin and the regulation of glucose metabolism

Abstract

OverviewThe identification of the ob gene through positional cloning [1] and the discovery that its encoded protein, leptin, is essential for body weight homeostasis [2±4] have permanently altered the field of metabolic physiology. Over a 5-year period a substantial and rapidly changing body of knowledge has been created.Leptin, a 16 kDa circulating hormone produced and released primarily by adipocytes, exerts a regulatory control on food intake and energy expenditure [2±4]. Plasma leptin concentrations are correlated with total fat mass, per cent body fat and body mass index acting as a sensing hormone or ªlipostatº in a negative feedback control from adipose tissue to the hypothalamus, the brain centre responsible for satiety [5,6]. Thus, leptin informs the brain about the abundance of body fat, thereby allowing feeding behaviour, metabolism and endocrine physiology to be coupled to the nutritional state of the organism. Leptin-deficient ob/ob mice exogenously treated with leptin have a pronounced body weight loss with a distinct loss of discernible body fat [2±4]. This effect is not only attributable to a decreased food intake but also to an increased basal metabolic rate with selective promotion of fat metabolism [2, 7±10].Leptin was discovered through a very specific biological action consisting in its involvement in body weight and appetite regulation. Interestingly, leptin has structural similarities to the family of helical cytokines [11]. Many cytokines, originally isolated through particular biological actions, have subsequently been shown to be capable of stimulating a variety of biological responses in a wide spectrum of cell types. Thus, leptin shares with other cytokines an extreme functional pleiotropy and has been shown to be involved in quite diverse physiological functions, such as reproduction [12], angiogenesis [13], haematopoiesis [14] and immune responsiveness [15].Consistent with leptin's role in controlling appetite and energy metabolism, leptin receptors (OB-R) have been found in the hypothalamus and adjacent brain regions [16,17]. At the beginning direct leptin actions were thought to be exclusively confined to the central nervous system (CNS). The almost ubiquitous distribution of functional OB-R provides, however, evidence for a multiplicity of peripheral target organs. At the cellular level OB-R, structurally related to the family of cytokine receptors, have been found to activate Janus kinases and to function as a signal transducer and activator of transcription (STAT) pathways [16]. Special attention among the extraneural tissues expressing functional OB-R should be given to organs involved in metabolism and digestion like the pancreas, skeletal muscle and the gastrointestinal system [16,17]. The pancreas has evolved a complex and exquisitely sensitive mechanism for matching the stimulation or inhibition of pancreatic hormone release to the prevailing metabolic needs [18]. Pancreatic endocrine and exocrine secretion is released in response to nutrient inflow from the gut and to g...

Serum leptin levels in patients with primary hyperaldosteronism before and after treatment: relationships to insulin sensitivity

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Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester

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Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility

“…Leptin, a major hormone secreted by white adipose tissue (WAT) (Zhang et al 1994), has been implicated in the regulation of body weight (Baskin et al 2001, Mantzoros 2001, glucose metabolism (Fruhbeck & Salvador 2000, Al-Daghri et al 2002, Ceddia et al 2002 and fertility (Brann et al 2002, Moschos et al 2002. Leptin null, Lep ob /Lep ob mice are obese, hyperphagic and insulin resistant (Coleman 1978).…”