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Relation Between Leptin and the Regulation of Glucose Metabolism

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Relation Between Leptin and the Regulation of Glucose Metabolism Diabetologia (2000) 43: 3±12 Ó Springer-Verlag 2000 Review Relation between leptin and the regulation of glucose metabolism G.Frühbeck, J.Salvador Department of Endocrinology, University Clinic, University of Navarra, Pamplona, Spain Keywords Leptin, ob gene, insulin, glucagon, chole- also to an increased basal metabolic rate with selec- cystokinin, glucose homeostasis, obesity, satiety. tive promotion of fat metabolism [2, 7±10]. Leptin was discovered through a very specific bio- logical action consisting in its involvement in body Overview weight and appetite regulation. Interestingly, leptin has structural similarities to the family of helical cyto- The identification of the ob gene through positional kines [11]. Many cytokines, originally isolated cloning [1] and the discovery that its encoded protein, through particular biological actions, have subse- leptin, is essential for body weight homeostasis [2±4] quently been shown to be capable of stimulating a va- have permanently altered the field of metabolic phys- riety of biological responses in a wide spectrum of cell iology. Over a 5-year period a substantial and rapidly types. Thus, leptin shares with other cytokines an ex- changing body of knowledge has been created. treme functional pleiotropy and has been shown to Leptin, a 16 kDa circulating hormone produced be involved in quite diverse physiological functions, and released primarily by adipocytes, exerts a regula- such as reproduction [12], angiogenesis [13], haema- tory control on food intake and energy expenditure topoiesis [14] and immune responsiveness [15]. [2±4]. Plasma leptin concentrations are correlated Consistent with leptin's role in controlling appetite with total fat mass, per cent body fat and body mass and energy metabolism, leptin receptors (OB-R) index acting as a sensing hormone or ªlipostatº in a have been found in the hypothalamus and adjacent negative feedback control from adipose tissue to the brain regions [16, 17]. At the beginning direct leptin hypothalamus, the brain centre responsible for sati- actions were thought to be exclusively confined to ety [5, 6]. Thus, leptin informs the brain about the the central nervous system (CNS). The almost ubiq- abundance of body fat, thereby allowing feeding be- uitous distribution of functional OB-R provides, haviour, metabolism and endocrine physiology to be however, evidence for a multiplicity of peripheral tar- coupled to the nutritional state of the organism. Lep- get organs. At the cellular level OB-R, structurally tin-deficient ob/ob mice exogenously treated with related to the family of cytokine receptors, have leptin have a pronounced body weight loss with a dis- been found to activate Janus kinases and to function tinct loss of discernible body fat [2±4]. This effect is as a signal transducer and activator of transcription not only attributable to a decreased food intake but (STAT) pathways [16]. Special attention among the extraneural tissues expressing functional OB-R should be given to organs involved in metabolism Corresponding author: G. Frühbeck, R Nutr MD PhD, Dept. and digestion like the pancreas, skeletal muscle and of Endocrinology, Clínica Universitaria de Navarra, Avda. the gastrointestinal system [16, 17]. The pancreas has Pío XII 36, 31008-Pamplona, Spain evolved a complex and exquisitely sensitive mecha- Abbreviations: OB-R, Leptin receptors; CNS, central nervous nism for matching the stimulation or inhibition of system; STAT, signal transducer and activator of transcription; pancreatic hormone release to the prevailing meta- GLP-1, glucagon-like peptide 1; PI3, phosphatidylinositol-3; bolic needs [18]. Pancreatic endocrine and exocrine NEFA, non-esterified fatty acids; UCP, uncoupling proteins; PEPCK, phosphoenolpyruvate carboxykinase; ICV, intracere- secretion is released in response to nutrient inflow broventricular; IRS, insulin-receptor substrate; GLUT, glu- from the gut and to gastrointestinal secretagogues. cose transport. Even though the insulo-acinar axis has been exten- 4 G.Frühbeck, J.Salvador: Leptin and glucose homeostasis Fig.1. Proposed model of the interrelations between nutri- ance between the rates of whole body glucose pro- tional, neural and hormonal factors working together on pan- duction and utilization. Each of these processes is creatic islet cells tightly regulated by the concentrations of hormones and substrates in blood. Functional OB-R have been shown to be expressed in pancreatic islets [23, 24]. This points to the possibility of leptin involvement in sively studied, the mechanisms of the regulation of local metabolic regulation. In this context, research- pancreatic secretion have not been fully assessed. In ers have evaluated the possible physiological role of this review the complex relation between leptin and leptin on the endocrine pancreas. insulin in the regulation of glucose metabolism is dis- cussed in the broader perspective of integrative phys- Leptin action on insulin production and release. The iology (Fig.1). relation between leptin and insulin seems to be com- Leptin inhibits food intake, reduces body weight, plex. Some researchers failed to show a direct effect stimulates energy expenditure and decreases hyper- of leptin on the release of either insulin or glucagon glycaemia and hyperinsulinaemia in obese rodents in the isolated perfused rat pancreas [25]. Other stud- [2±4]. It was also observed that changes in glycaemia ies provide, however, evidence that leptin can directly precede changes in body weight [2]. In addition, inhibit both basal and glucose-stimulated insulin se- pair-feeding studies [7] and experimental hyperlepti- cretion [23, 24]. As depicted in Figure 2, leptin inhib- naemic animal models [19, 20] provide compelling its insulin secretion by acting on ATP-sensitive potas- evidence that leptin exerts an appreciable metabolic sium channels [26, 27], a mechanism later reported to regulatory role, in addition to appetite suppression. mediate leptin action in the hypothalamus [28]. The It has been shown that leptin is involved in the regula- inhibitory effect of leptin on insulin secretion does tion of glucose transport [21, 22]. The importance of not seem to be due to major actions on the main glu- glucose transport as the rate-limiting step in whole cose-phosphorylating pathways in the beta cells as body glucose utilization becomes more important in no changes in hexokinase and glucokinase activities metabolic disease states such as obesity and Type II have been observed [29] and glucokinase regulation (non-insulin-dependent) diabetes mellitus, in which appears to be leptin-independent [30]. Arginine-in- insulin-mediated glucose transport is impaired. Al- duced insulin production did not seem to be affected though leptin has been shown to increase whole by leptin in vitro [29] suggesting that, at least some body glucose utilization, the effect of leptin on glu- of the mechanisms through which amino acids induce cose at the tissue level remains controversial. insulin release are not influenced by leptin. A possi- ble participation of leptin in amino acid-stimulated insulin production under physiological circumstances Leptin action on pancreatic islets cannot, however, be ruled out. Leptin has been shown to specifically target the Plasma glucose concentration is tightly controlled phospholipase C/protein kinase C-mediated regula- throughout life under physiological conditions. This tory component of insulin secretion rather than the precise control is best seen during periods of food glucose or protein kinase A signalling components deprivation or consumption. The stability of the plas- of the secretory process [31]. Leptin constrained the ma glucose concentration is a reflection of the bal- enhanced phospholipase C-mediated insulin secre- G.Frühbeck, J.Salvador: Leptin and glucose homeostasis 5 tion characteristic of islets from ob/ob mice, without The existence of a direct suppressive effect of leptin influencing release from islets of lean mice. A specific on insulin production at the level of both stimulus-se- enhancement in phospholipase C-mediated insulin cretion coupling and gene expression as well as the secretion is the earliest reported developmental alter- antagonism between leptin and GLP-1 signalling on ation in insulin secretion from islets of ob/ob mice beta cells have been further shown in human islets and thus a logical target for leptin action. This effect [41]. These findings support the leptin-related effec- of leptin on phospholipase C-mediated insulin secre- tors of insulin secretion operating in rodents being tion has been reported to be dose-dependent, rapid equivalent to those in humans. in onset (within about 3 min) and reversible [31]. Furthermore, leptin could inhibit long-term stimu- Leptin was equally effective in constraining the en- lation of preproinsulin gene expression during the hanced insulin release from islets of ob/ob mice fasting state. The inhibitory actions of leptin on pre- caused by protein kinase C activation, a downstream proinsulin gene expression appear to be transmitted mediator of the phospholipase C signalling pathway. through an intracellular signalling pathway that dif- Therefore, one function of leptin in body composi- fers from the one affecting ATP-sensitive potassium tion control could be to target a protein kinase C-reg- channels and with different sensitivity to ambient glu- ulated component of the phospholipase C/protein ki- cose concentrations [39]. Whereas short-term inhibi- nase C signalling system within
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