The effect of acute exposure to cold on the expression of the ob (obese) gene, which encodes a protein that plays a critical role in the regulation of energy balance and body weight, has been examined in epididymal white adipose tissue of mice. Overnight (18 h) exposure of mice to a temperature of 4 degrees C led to the disappearance of ob mRNA in epididymal white fat, and subsequent studies showed that a cold-induced loss of ob mRNA could occur in as little as 2-4 h of exposure to 4 degrees C. When mice exposed to cold for 18 h were returned to the warm (24 degrees C), there was a rapid stimulation of the expression of the ob gene, the mRNA returning within 2.5 h. Administration of noradrenaline led to a reduction in the level of ob mRNA in mice maintained in the warm, while isoprenaline resulted in the disappearance of the mRNA; these changes in ob mRNA were paralleled by similar changes in lipoprotein lipase mRNA. In contrast to white fat, the level of lipoprotein lipase mRNA in brown adipose tissue was increased by noradrenaline and isoprenaline. It is concluded that there is a cold-induced suppression of ob gene expression in white adipose tissue of mice and that this is mediated primarily by the sympathetic system. The profound effect of cold on ob gene expression indicates that the ob system relates to energy expenditure, as well as to satiety.

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Leptin is secreted primarily from white adipose tissue and stimulates long-form OB-Rb receptors in the hypothalamus to decrease food intake and increase energy expenditure. A variety of neuropeptides are involved in these responses, including neuropeptide Y, agouti-related protein, the prepro-melanocortin system and cocaine- and amphetamine-regulated transcript. OB-Rb receptors (and other receptor isoforms) are also found in peripheral tissues. Leptin is now known to have a wide range of peripheral actions and is involved in activating the immune system, haematopoiesis, angiogenesis and as a growth factor, as well as being a regulator of many cellular functions. The identification of leptin has led to reappraisal of the role of white adipose tissue from being an organ concerned primarily with energy storage as fat to an understanding that it is also a major endocrine and secretory organ. While the importance of the sympathetic nervous system in mobilising fatty acids from adipose tissue has long been known, it has become apparent that the sympathetic system is a key regulator of leptin production in white adipose tissue as well. Sympathomimetic amines and cold exposure or fasting (which lead to sympathetic stimulation of white fat), decrease leptin gene expression in the tissue and leptin production. On the other hand, sympathetic blockade often increases circulating leptin and leptin gene expression, and it is possible that the sympathetic system has a tonic inhibitory action on leptin synthesis. Apart from the few instances where leptin is absent, leptin levels are increased in obesity, while the sympathetic sensitivity of adipose tissue is reduced, consistent with the high leptin levels that are seen. The dysregulation of energy balance leading to obesity may partly involve a decrease in leptin sensitivity, or the leptin system may be set to have maximal effects at low leptin levels.

The discovery of leptin, the product of the ob gene, has led to major developments in understanding the regulation of energy balance. It is now recognised that leptin is produced in several organs additional to white adipose tissue, including brown fat, the placenta and fetal tissues (such as heart and bone/cartilage). The hormone has multiple functions-in inhibiting food intake, in the stimulation/maintenance of energy expenditure, as a signal to the reproductive system and as a 'metabolic' hormone influencing a range of processes (for example, insulin secretion, lipolysis, sugar transport). The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production by white fat is envisaged for the sympathetic system, operating through beta3-adrenoceptors. The leptin receptor gene is widely expressed, with the several splice variants exhibiting different patterns of expression. The long form variant (Ob-Rb) is expressed particularly in the hypothalamus, although it is being increasingly identified in other tissues. Leptin exerts its central effects through several neuroendocrine systems, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotrophin releasing hormone (CRH) and cocaine- and amphetamine-regulated transcript (CART). In essence, the leptin system now appears highly complex, the hormone being involved in a range of physiological processes in a manner far transcending the initial lipostatic concept. This complexity may reduce the potential of the leptin system as a target for anti-obesity therapy.

The anorexigenic and orexigenic hormones leptin and ghrelin act in opposition to one another. When leptin signaling is reduced, as in the Zucker fatty rat, or when circulating ghrelin is increased during fasting, the effect of ghrelin becomes more dominant, indicating an influence of both hormones on ghrelin action. This effect could be mediated via the level of expression of ghrelin receptor (growth hormone secretagogue receptor [GHS-R]). For testing this, GHS-R expression was measured using in situ hybridization in Zucker fatty versus lean rats; in fed versus fasted (48 h) rats, treated with either ghrelin or leptin; and in GH-deficient, dwarf versus control rats. In the arcuate nuclei of the Zucker fatty rat and in fasted rats, GHS-R expression is significantly increased. A single leptin intracerebroventricular injection attenuated the fasting-induced increase in GHS-R but had no effect in fed rats 2 h after injection, whereas leptin infusion for 24 h or longer significantly decreased GHS-R expression in fed rats. Ghrelin significantly increased GHS-R expression but not in dwarf rats. These results show that the level of GHS-R expression in the ARC is reduced by leptin and increased by ghrelin and that the effect of ghrelin may be GH dependent.

Leptin receptor gene expression has been measured in arcuate and ventromedial hypothalamic nuclei. Receptor mRNA in both hypothalamic areas was higher in obese mice than in lean littermates. Twice daily leptin administration for 7 days profoundly affected food intake, reduced leptin receptor mRNA in the arcuate nucleus, and had a similar effect on neuropeptide Y gene expression. A single leptin injection was ineffective. Exposure of lean mice to cold for 24 h caused an induction of leptin receptor and NPY mRNA which was normalized when animals were returned to the warm. Regulation of receptor gene expression may be an important component in the reading of the leptin signal.

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