Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance

Obesity-related leptin resistance manifests in loss of?leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the?kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.     

运动改善肥胖症瘦素抵抗及其机制研究进展

大部分肥胖患者体内出现瘦素抵抗,表现为血清瘦素水平异常升高,但机体对瘦素不敏感或无反应,使瘦素抑制食欲、增加能量消耗和降低血糖等功能不能有效发挥.减轻瘦素抵抗被认为是治疗肥胖及肥胖相关疾病的有效途径.运动减轻肥胖、改善糖脂代谢和增强胰岛素敏感性的作用与运动降低瘦素水平、改善瘦素抵抗密切相关.本文在概述瘦素实现生理功能的机制、肥胖症的中枢及外周瘦素抵抗的基础上,主要综述近年来运动减轻肥胖症瘦素抵抗机制的研究进展,包括减轻高瘦素血症、改善中枢和外周瘦素抵抗,以期为运动防治肥胖机制的研究提供新视角.     

Rethinking leptin and insulin action: therapeutic opportunities for diabetes

Leptin is an adipocyte-derived hormone that primarily acts in the hypothalamus and plays a key role in the regulation of food intake, body weight, energy expenditure and neuroendocrine function. Leptin has direct peripheral effects on several tissues, and it may be independently involved in insulin secretion and action besides its effects on body weight regulation. Basal plasma leptin and insulin concentrations correlate with each other. Insulin and glucose appear to increase leptin secretion. In turn, leptin increases peripheral insulin sensitivity while decreasing insulin secretion from pancreatic beta cells. Leptin increases skeletal muscle glucose uptake and oxidation, and suppresses hepatic glucose output. Effects of leptin on lipid metabolism might reduce lipotoxicity and therefore contribute to the improvement of hepatic, skeletal and whole body insulin sensitivity. Leptin is the first adipokine used in the treatment of hypoleptinemic clinical disorders. Although leptin therapy has limited success in common obesity, it has impressive effects in congenital leptin deficiency, lipoatrophic diabetes and syndromes of severe insulin resistance. Leptin has been reported to ameliorate hyperinsulinemia and diabetes in the clinical setting of congenital leptin deficiency. It also improves hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia and hepatic steatosis in lipoatrophic diabetes. These promising results warrant clinical trials to test the hypothesis that leptin alone or with classical antidiabetic agents may potentially be beneficial in the treatment of hypoleptinemic non-obese individuals with glucose intolerance and diabetes. This review summarizes the clinical applications of leptin, particularly emphasizing the effects of leptin on glucose homeostasis.     

Leptin signaling pathways in the central nervous system: interactions between neuropeptide Y and melanocortins.

No other hormone has drawn more attention than leptin in recent studies on the control of appetite, body weight and obesity. This hormone is produced by adipose tissue and enters the brain via a saturable specific transport mechanism. Leptin acts in the hypothalamus to modulate food intake and heat production as well as several other neuroendocrine pathways. The mechanisms through which leptin exerts its central nervous effects are now better understood. Proopiomelanocortin- and neuropeptide Y-containing neurons in the hypothalamus have emerged as potent candidate mediators of leptin action. These two neuropeptides have been shown to exert opposing effects using different pathways. Recently, Cowley et al. (2001) described a new circuit in the regulation of neuronal activity by leptin with an interaction between these two pathways. These data add complexity to the mechanisms by which leptin achieves its effects in the central nervous system, but they also offer potential mechanisms to explain the phenomenon of leptin resistance observed in obesity.     

Role of leptin in reproduction

PURPOSE OF REVIEW: This article focuses on recently gained knowledge concerning the different emerging aspects of the role of leptin in reproduction, through both its central hypothalamus-mediated and peripheral actions. RECENT FINDINGS: As delineated in murine models, STAT3-independent signals triggered by the leptin receptor are clearly important in fertility, and candidate pathways such as those via phosphatidylinositol-3 kinase and extracellular signal-related kinase are implicated in leptin-regulated cascades. Another aspect whose importance has recently been revealed is that of the bioavailability of leptin in general, and the fate and action of carrier-bound versus free leptin at central and peripheral sites in particular. SUMMARY: Besides the well-established role of leptin in the control of appetite and energy expenditure in humans and animals, evidence for a major involvement of the hormone in the function of the reproductive system is rapidly accumulating through physiological and molecular genetic approaches. Powerful animal models that facilitate the dissection of increasingly complex pathways, together with detailed studies in man, will soon delineate in detail the diverse roles of leptin in biological regulation. The development of therapeutic agents primarily directed against obesity must therefore take into consideration the consequences of treatment not only on the amelioration of leptin resistance, but also on the bioactivity of leptin in the context of growth, glucose homeostasis, and last but not least, fertility.     

The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis

The hormone leptin plays a crucial role in maintenance of body weight and glucose homeostasis. This occurs through central and peripheral pathways, including regulation of insulin secretion by pancreatic beta cells. To study this further in mice, we disrupted the signaling domain of the leptin receptor gene in beta cells and hypothalamus. These mice develop obesity, fasting hyperinsulinemia, impaired glucose-stimulated insulin release, and glucose intolerance, similar to leptin receptor null mice. However, whereas complete loss of leptin function causes increased food intake, this tissue-specific attenuation of leptin signaling does not alter food intake or satiety responses to leptin. Moreover, unlike other obese models, these mice have reduced fasting blood glucose. These results indicate that leptin regulation of glucose homeostasis extends beyond insulin sensitivity to influence beta cell function, independent of pathways controlling food intake. These data suggest that defects in this adipoinsular axis could contribute to diabetes associated with obesity.     

Obesity reduced the gene expressions of leptin receptors in hypothalamus and liver.

The expression of leptin receptor (OB-R) is downregulated by leptin in some cell lines. This study investigated the expressions of leptin receptors at central nerve system and peripheral site in a dietary model of obesity. Rats in the 8 week high-diet and control group were classified based on body weight gain into obese and control groups. Serum leptin and insulin concentrations were measured and gene expressions of short form of leptin receptor (OB-Ra) and long form (OB-Rb) in hypothalamus and liver were detected by RT-PCR. The levels of serum leptin in obese rats were increased compared with control rats (p<0.05). The levels of OB-Ra and OB-Rb gene expressions in both hypothalamus and liver in obese rats were reduced significantly (p<0.01). Serum leptin concentrations of obese rats had a significant negative relationship with both of OB-Ra or OB-Rb gene expression levels in hypothalamus and liver (p<0.01). On the other hand, serum insulin levels had no relationship with OB-Ra or OB-Rb gene expression levels in neither liver nor hypothalamus. Rats with diet-induced obesity have hyperleptinemia and reduced expressions of leptin receptors in hypothalamus and liver. The results suggest that a leptin downregulated OB-R expression is one of leptin resistant mechanisms for maintaining obesity.     

From the conceptual basis to the discovery of leptin

Two years ago, the Lasker Award was shared by Douglas Coleman and Jeffrey Friedman for their discovery of leptin, a hormone that exerts a key role in the central regulation of appetite and body weight. Douglas Coleman is recognized as the researcher who raised the hypothesis and predicted that a circulating satiety factor was lacking in the ob/ob mouse, and predicted that this factor acted at the hypothalamic level to modulate food intake. After three decades, in an attempt to identify the genes that were mutated in the ob/ob mouse, Jeffrey Friedman found that the ob gene encodes a protein hormone that reverses obesity and other abnormalities of this genetic rodent model of obesity. This discovery was a landmark event in physiology, and revolutionized our understanding of energy homeostasis. This short review aims to summarize the main steps that lead to the identification of leptin, the product of the ob gene.     

Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis

Leptin, an adipocyte-derived hormone, acts directly on the brain to control food intake and energy expenditure. An important question is the identity of first-order neurons initiating leptin's anti-obesity effects. A widely held view is that most, if not all, of leptin's effects are mediated by neurons located in the arcuate nucleus of the hypothalamus. However, leptin receptors (LEPRs) are expressed in other sites as well, including the ventromedial hypothalamus (VMH). The possible role of leptin acting in "nonarcuate" sites has largely been ignored. In the present study, we show that leptin depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-positive neurons in the VMH. We also show, by generating mice that lack LEPRs on SF1-positive neurons, that leptin action at this site plays an important role in reducing body weight and, of note, in resisting diet-induced obesity. These results reveal a critical role for leptin action on VMH neurons.     

Cardiovascular effects of leptin and orexins

Leptin, the product of the ob gene, is a satiety factor secreted mainly in adipose tissue and is part of a signaling mechanism regulating the content of body fat. It acts on leptin receptors, most of which are located in the hypothalamus, a region of the brain known to control body homeostasis. The fastest and strongest hypothalamic response to leptin in ob/ob mice occurs in the paraventricular nucleus, which is involved in neuroendocrine and autonomic functions. On the other hand, orexins (orexin-A and -B) or hypocretins (hypocretin-1 and -2) were recently discovered in the hypothalamus, in which a number of neuropeptides are known to stimulate or suppress food intake. These substances are considered important for the regulation of appetite and energy homeostasis. Orexins were initially thought to function in the hypothalamic regulation of feeding behavior, but orexin-containing fibers and their receptors are also distributed in parts of the brain closely associated with the regulation of cardiovascular and autonomic functions. Functional studies have shown that these peptides are involved in cardiovascular and sympathetic regulation. The objective of this article is to summarize evidence on the effects of leptin and orexins on cardiovascular function in vivo and in vitro and to discuss the pathophysiological relevance of these peptides and possible interactions.     

Action of leptin on bone and its relationship to menopause

Backround: Leptin a cytokine protein secreted by adipose tissue raises considerable interest as a potential mediator of the protective effects of fat mass on bone tissue. After menopause heavier women conserve bone mass better than those with lower body weight. The protective effect of obesity on bone mass has been ascribed to a high body fat content. As Leptin levels reflect the body fat content it has emerged as a possible mediator of these protective effects. Methods: A search of the available literature focused on the role of leptin on bone tissue. Results: Both peripheral and central action of leptin on bone metabolism have been proposed. In vitro and in vivo evidence supports the hypothesis that leptin can act directly or indirectly on bone remodelling by modulating both osteoblast and osteoclast activities. However, studies in humans have not yet been able to confirm these actions possibly because of the shifting balance between stimulatory direct action and suppressive indirect action of leptin on bones via the hypothalamus. The effects of oestrogen decline and deficiency during natural or artificially induced menopause and administration of hormone replacement therapy has on leptin production remains controversial. Various studies have shown differences in leptin values in pre- and postmenopausal women. The existing clinical data on this issue are discordant. Conclusion: Larger clinical studies are necessary to clarify leptin's role in vivo and to assess the contribution of the central and peripheral role of leptin in the overall maintenance of bone turnover in human beings.     

The role of leptin in striped hamsters subjected to food restriction and refeeding

Food restriction(FR) and refeeding(Re) have been suggested to impair body mass regulation and thereby making it easier to regain the lost weight and develop over-weight when FR ends. However, it is unclear if this is the case in small mammals showing seasonal forging behaviors. In the present study, energy budget, body fat and serum leptin level were measured in striped hamsters that were exposed to FR-Re. The effects of leptin on food intake, body fat and genes expressions of several hypothalamus neuropeptides were determined. Body mass, fat content and serum leptin level decreased during FR and then increased during Re. Leptin supplement significantly attenuated the increase in food intake during Re, decreased genes expressions of neuropepetide Y(NPY) and agouti-related protein(AgRP) of hypothalamus and leptin of white adipose tissue(WAT). Hormone-sensitive lipase(HSL) gene expression of WAT increased in leptin-treated hamsters that were fed ad libitum, but decreased in FR-Re hamsters. This indicates that the adaptive regulation of WAT HSL gene expression may be involved in the mobilization of fat storage during Re, which partly contributes to the resistance to FR-Re-induced overweight. Leptin may be involved in the down regulations of hypothalamus orexigenic peptides gene expression and consequently plays a crucial role in controlling food intake when FR ends.     

Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway

Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu(-/-) mice) develop obesity. Nmu(-/-) mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu(-/-) mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu(-/-) mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity.     

Peripheral but not central leptin treatment increases numbers of circulating NK cells, granulocytes and specific monocyte subpopulations in non-endotoxaemic lean and obese LEW-rats

Leptin, a hormone mainly generated by adipocytes, acts centrally in the hypothalamus to regulate body weight and energy expenditure. However, there is strong evidence that leptin is also involved in cell-mediated immunity and cytokine crosstalk. In the present study the effects of diet-induced obesity and central and peripheral leptin treatment on leukocyte subsets and cytokine production was investigated. Leptin was injected either intravenously (i.v.) or intracerebroventricularly (i.c.v.) in male endotoxaemic or vehicle-treated healthy LEW-rats. Numbers of blood leukocyte subsets were analysed by FACS and cytokines (TNF-alpha and IL-6) by ELISA. Results showed that peripheral rather than central leptin treatment was able to significantly increase numbers of granulocytes, NK cells and monocytes. Three-colour staining revealed that the increase of ED9(+) monocytes was most likely due to the mobilization of two distinct monocyte subsets, predominantly ED9(+)CD4(-)NKR-P1A(+) and ED9(+)CD4(+)NKR-P1A(+). ELISA analysis revealed significantly elevated TNF-alpha levels in obese animals compared to their lean littermates, while IL-6 failed to show notable changes. In conclusion, the data of the present study revealed that leptin application induces a nutrition- and application-site dependent increase of circulating NK cells, granulocytes and specific monocyte subsets.     

Lasker lauds leptin

This year, the Albert Lasker Basic Medical Research Award will be shared by Douglas Coleman and Jeffrey Friedman for their discovery of leptin, a hormone that regulates appetite and body weight. By uncovering a critical physiologic system, their discovery markedly accelerated our capacity to apply molecular and genetic techniques to understand obesity.     

Roles for melanocortins and leptin in adipose tissue apoptosis and fat deposition

Leptin has a wide range of effects on physiological functions related to the regulation of body energy balance. Many of leptin's effects are mediated through neuropeptide-containing neurons and neuropeptide receptors in the hypothalamus. The melanocortin system includes both agonist (alpha-melanocyte stimulating hormone, alphaMSH) and antagonist peptides (agouti related peptide, AGRP). Increased melanocortin receptor stimulation following leptin administration plays an important role in leptin-induced hypophagia and increased sympathetic nervous system activity and is partly responsible for leptin-induced weight loss. However, melanocortins do not appear to mediate some of the more striking centrally-mediated effects of leptin on adipose tissue, including adipose tissue apoptosis, that lead to the extensive depletion of fat.     

Direct delivery of leptin to the hypothalamus using recombinant adeno-associated virus vectors results in increased therapeutic efficacy

The hormone leptin has been shown to be an afferent signal in a negative-feedback loop regulating body weight, and consequently, the administration of the gene product for the treatment of obesity has recently attracted considerable attention. Leptin is produced by adipocytes in response to increased trigyceride storage, and appears to affect body weight primarily through target cells in the hypothalamus. Although plasma levels of leptin correlate positively with adipose tissue mass in normal humans and animals, recent studies have shown that obese humans and animals appear to be relatively resistant to the increased plasma levels of leptin. Analysis of the levels of leptin in the cerebrospinal fluid suggests that the uptake of leptin across the blood-brain barrier may be saturable. Taken together, these results suggest that therapeutic approaches to deliver leptin through the circulation may prove to be problematic. Although recent clinical trials have suggested that peripherally administered leptin might lead to a reduction in body weight in humans, it is likely that the more effective delivery of leptin to cellular targets within the central nervous system will be necessary in order to fully reveal the therapeutic potential of the gene product. In an effort to provide a means for the delivery of leptin that obviates the need for the gene product to traverse the blood-brain barrier, we have evaluated the use of recombinant adeno-associated vectors to deliver leptin intraventricularly or directly to the hypothalamus.