Leptin and resistin: master enemy adipokines unified in brain to control glucose homeostasis.

Metabolic diseases diabetes and obesity are the consequence of an impaired balance between energy uptake and energy dissipation. The1 intimate mechanisms controlling energy homeostasis depend on hormonal and neural systems. In the 1850s, Claude Bernard established first the important role of the brain on the control of glucose homeostasis (1). Later on, during the 1920s, Banting and Best (2) uncovered a key molecule from the pancreas, i.e. insulin. Ever since, pancreatic and brain functions were the leading physiological mechanisms for the control of energy homeostasis. However, over the last two decades, numerous adipose secreted proteins have been shown to behave as hormones and to control glucose metabolism. Leptin, discovered by J. Friedman in 1994, has, ever since, drawn most of the attention (3). This protein, consecutively secreted in response to hyperinsulinemia after a meal, inhibits food intake by triggering cells in the arcuate nucleus of the hypothalamus (4) and increases glucose oxidation and energy expenditure (5). It further activates whole-body glucose metabolism, targeting the liver and peripheral tissues to increase insulin sensitivity (5–7). Thereafter, numerous other secreted proteins have been identified (8). At the opposite physiological philosophy, resistin, another adipocyte-secreted hormone, induces insulin resistance because the administration of this adipokine to mice, or rodents expressing dominant-negative resistin, induces glucose intolerance and reduces insulin sensitivity (9, 10). Because leptin mediates most of its physiological effect by triggering cells in the arcuate nucleus of the hypothalamus in this issue, Park et al. (11) suggested that resistin could modulate hypothalamic leptin action. Furthermore, the authors asked the important question as to whether the resistin regulation of hypothalamic leptin signaling and action would contribute to the progression of the diabetic status. Rats were infused for 4 wk with leptin/resistin into the lateral ventricle of the brain. Over a large set of experiments, peripheral insulin sensitivity and pancreatic -cell function and mass was assessed in rodents fed a high-fat diet or pancreatectomized to induce diabetes. The striking results are that central leptin signaling improves whole-body glucose metabolism by augmenting peripheral insulin sensitivity, whereas central resistin signaling also improves wholebody glucose homeostasis but by a mechanism that mostly involves insulin secretion (11). Hence, brain infusion of both adipokines positively impacts diabetes because the glycemic levels are quickly reduced during oral glucose tolerance when compared with rats not infused with adipokines. In addition, it is further demonstrated that resistin prevents the loss of -cell function in diabetic rats (11). Another important opposition between both adipokines is that central resistin offsets the effect of central leptin on insulin sensitivity; hence, this further demonstrates the counterintuitive effect of these adipokines on the improvement of glucose metabolism during diabetes. The opposite effect of leptin and resistin in the brain was demonstrated by analyzing the signaling pathways of both cytokines in the hypothalamus. Leptin increases and activates signal transducer and activator of transcription 3 and conversely decreases AMP-activated kinase phosphorylation and activation. Resistin does the contrary and in addition reduces the effect of leptin on these secondary messengers. From a finalistic point of view, it makes no sense that two adipokines with opposite mechanism lead to a similar effect, i.e. improved glucose homeostasis during diabetes unless one makes a different conclusion and a new hypothesis. It is conceivable that leptin is now considered as a hormone positively involved in the regulation of wholebody energy homeostasis during physiological situations such as for the control of everyday feeding behavior, thermogenesis, or energy expenditure (Fig. 1). With regard to resistin, it is noteworthy that this adipokine is oversecreted in diet-induced and genetic forms of obesity, therefore, in a pathological situation. Circulating resistin levels are decreased by the antidiabetic drug rosiglitazone, and the administration of antiresistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Thus, it is conceivable that this adipokine could have a regulatory role in pathological situations mainly, where it could contribute to induce insulin resistance. As demonstrated by Park et al. (11), central resistin signaling increases glucose-induced insulin secretion and -cell mass. Therefore, by simultaneously inducing insulin resistance and hyperinsulinemia, resistin allows the body to adapt to obesity by favoring -cell function, i.e. mass and secretion (Fig. 1). The absence of a diabetogenic effect of resistin could be due to its duality of action on insulin resistance and on insulin secretion. Because obesity is associated with a state of leptin resistance, the effectiveness of resistin during this pathological situation to maintain normal blood glucose homeostasis would prevent the outcome of diabetes and also further enhance the development of adipose tissue by means of hyperinsulinemia. The efficacy of resistin to impact energy metabolism during obesity, when compared with leptin, could reside in the fact that not only the central signaling pathways between the two adipokines are different but also that resistin further nullifies central leptin signaling, as shown in this issue (11). This point is of major importance because central leptin reduces the -cell mass. Therefore, resistin, by nullifying the leptin effect, prevents the reduction of -cell mass by leptin and allows hyperinsulinemia, which overcome insulin resistance during obesity and hence enhances the development of adiposity. Furthermore, one should not consider that an increased adSee article p. 445. 0013-7227/08/$15.00/0 Endocrinology 149(2):443–444 Printed in U.S.A. Copyright © 2008 by The Endocrine Society doi: 10.1210/en.2007-1507