Despite of the receptor expression, however, a direct action of leptin on gastric epithelial cell function is insufficiently understood. Notably, the protection conferred by leptin is as effective as that by CCK-8, a potent gastric protector Mirza et al. Several studies using rodent models highlight possible mechanisms. Nevertheless, unlike its protective effects against gastric injury, leptin appears to accelerate immune responses during gastric inflammation by synergistically interacting with a number of proinflammatory cytokines.
Inagaki-Ohara et al. Leptin has been implicated in several experimental models of Helicobacter pylori infection, which is the major cause of chronic gastritis and peptic ulcer diseases Kang and Kim, Several clinical studies have demonstrated that mucosal leptin levels are significantly elevated in H. Using biopsy samples of H. Leptin has been shown to modulate intestinal functions, mostly via its action on CNS as well as its regulation of vagal afferent sensitivity to intestinal signals Huang et al.
Significant expression of LepRb, the longest functional isoform, has been detected in Caco-2 and rat intestinal mucosal cells Buyse et al. In the intestine, leptin has been shown to control the absorption of macronutrients. Although leptin decreases carbohydrate absorption during the pre-prandial state, leptin increases carbohydrate absorption during the postprandial state via increased expression of carbohydrate transporters, glucose transporter 2 GLUT-2 , GLUT-5, and sodium-glucose cotransporter-1 SGLT-1 Pearson et al.
Leptin also increases protein absorption via activation of the proton-dependent di- and tri-peptide transporter PepT1 Buyse et al. In contrast, following food ingestion, leptin reduces lipid release into the circulation by suppressing apolipoprotein Apo A-IV Doi et al. Leptin is required for gut development and maintenance, as it functions as a growth factor for intestinal cells Martin and Devkota, Alavi et al. Several lines of evidence indicate that leptin improves tissue injury healing and mucosal defense mechanisms.
A study using rat arteries suggested that the tissue healing effect of leptin may be attributed to its stimulation of nitric oxide production, which mediates vasodilation, which in turn assists wound healing Kimura et al. The common features of IBD include body weight loss, anorexia, and higher energy expenditure Sairenji et al.
As leptin is a central hormone involved in energy homeostasis and neuroendocrine function Francisco et al. These data indicate that systemic leptin signaling is activated in IBD. Multiple researches show that the increased leptin signaling activates immune responses leading to IBD aggravation, resulting in deleterious effects. Sitaraman et al. Not only proinflammatory responses, leptin may mediates anorexia and body weight loss in IBD.
In rats with TNBS-induced colitis, the severity of colitis is associated with circulating leptin levels as well as with anorexia and body weight loss Barbier et al. In mice with DSS-induced colitis, delayed puberty is observed in proportion with the changes in serum leptin concentration, food intake, and body weight Deboer and Li, Figure 2.
Unlike the other tissues discussed above, where the longest form, LepRb, is highly expressed, the liver appears to only express short forms of LepRs Zhao et al. The absence of functional LepRb indicates that liver is unlikely a direct target of leptin. However, leptin has been shown to interact with various hepatic metabolic pathways, such as glucose and lipid metabolism, possibly via its function in the CNS da Silva et al.
Leptin controls glucose homeostasis by suppressing the hepatic de novo gluconeogenesis and lipogenesis and increasing hepatic triglyceride secretion Denroche et al.
Leptin prevents hepatic lipotoxicity by confining the storage of triglycerides to adipocytes Unger et al. Aberrant leptin signaling has been implicated in non-alcoholic fatty liver diseases NAFLD such as hepatic steatosis, hepatitis, and fibrosis. Multiple studies conducted in rodents and humans have shown that leptin treatment may ameliorate hepatic fat accumulation, suggesting its anti-steatotic effect Paz-Filho et al.
Leptin also controls hepatic sympathetic nerve activity via activation of PI3K and AMPK signaling, which leads to improvement in the fatty liver disease Miyamoto et al. Despite these positive reports on the effect of leptin on the liver, the efficacy of leptin in preventing liver steatosis seems limited by obesity. This is due to leptin resistance, one of the major features observed in obese individuals, where circulating leptin levels are extremely high compared to those in lean individuals Izquierdo et al.
Despite high concentrations, leptin resistance leads to failure of leptin action, which inhibits the modulation of hepatic glucose metabolism and insulin response Engin, ; Rizwan et al. Increased fat mass in obesity causes chronic inflammation and increases the expression of numerous adipokines, including leptin. The increased leptin levels in obese status appear to boost hepatic pro-inflammatory and pro-fibrogenic responses, thus damaging the liver Saxena and Anania, The pro-fibrogenic action of leptin involves hepatic stellate cells HSCs , which are liver-specific pericytes Tsuchida and Friedman, Once activated, but not quiescent, HSCs express leptin Potter et al.
Despite this evidence in experimental in vitro and in vivo models, conflicting data have been obtained in human patients with NAFLD, regarding the role of leptin in hepatic inflammation and fibrosis Polyzos et al. However, leptin therapy has been actively used in patients with lipodystrophy, a disorder characterized by fat loss, severe insulin resistance, and NAFLD and steatohepatitis NASH Akinci et al.
Notably, patients with lipodystrophy display low circulating levels of leptin hypoleptinemia Chong et al. In , leptin replacement was initially tested in nine female patients with lipodystrophy, and the therapy was shown to be effective in treating the disease Oral et al. Specifically, leptin therapy improves glycemic control and decreases triglyceride levels, thus effectively improving the symptoms of NASH Polyzos et al. Leptin controls glucose homeostasis mainly via its actions on the hypothalamus D'souza et al.
Under steady-state conditions, leptin signaling in the CNS seems to govern pancreas physiology, rather than its direct action in pancreas. In INS-1 cells and in human pancreatic islets, Laubner et al. This notion was further supported by Pedroso et al. These proliferative effects of leptin are mediated by activation of the MAPK pathway and c-fos, which are critical regulators of the cell cycle Zhang and Liu, In rat islets, leptin increases intracellular fatty acid oxidation, and subsequently depletes triglyceride accumulation in islets, thereby preventing lipotoxicity-induced apoptosis Shimabukuro et al.
In addition, leptin reduces cellular nitric oxide levels by suppressing inducible NO synthase iNOS expression Okuya et al. This discrepancy between the anti- and pro-apoptotic effects of leptin may be due to different experimental designs.
Indeed, most pro-apoptotic effects were observed when the cells were chronically treated with leptin Maedler et al. Several in vivo studies have reported that leptin may exert a protective effect on pancreatitis. In the clinical setting, higher plasma leptin concentrations are associated with acute pancreatitis; thus, leptin may be a possible predictor of disease severity Konturek et al.
Leptin is also associated with persistent hyperglycemia, as shown in the early course of acute pancreatitis Kennedy et al. However, no clinical trials have examined exogenous leptin treatment in patients with acute pancreatitis Figure 4. In this section, we discuss the roles of leptin in the digestive system, including the stomach, intestine, liver, and pancreas.
The current knowledge indicates that leptin plays critical but complex roles in these tissues, where its action appears to differ in the physiological and pathological states Figure 1- 4. In addition, leptin exerts protective effects by supporting cell proliferation, improving tissue repair, and preventing non-adipocyte lipotoxicity.
However, leptin action is not always protective, particularly during pathologic conditions. Of note, relatively little has been investigated a direct action of leptin in the digestive system. Indeed, most of the studies have examined the effect of central or peripheral leptin administration, which activates leptin signaling in the central nervous system.
In that most of the leptin functions have been attributed to its action in the brain, there is no strong evidence to demonstrate leptin acts directly on peripheral tissues by binding receptors expressed in these tissues.
Further studies using tissue-specific knockout models to limit the receptor expression are highly warranted. Leptin replacement therapy is enormously beneficial in individuals with congenital leptin deficiency, which restores their energy homeostasis, neuroendocrine system, and glucose metabolism Perakakis et al. As mentioned above, leptin administration is also widely used in patients with lipodystrophy.
Since lipodystrophy is a medical condition characterized by degenerative adipose tissue, leptin production in patients is significantly reduced Grewal et al.
Therefore, administration of human recombinant leptin improves many metabolic defects in patients with lipodystrophy Petersen et al. Since its discovery, leptin has been considered an attractive therapeutic target for the treatment of obesity and type 2 diabetes, due to its potency for the endocrine control of energy balance Friedman, However, unlike that in congenital leptin deficiency, leptin concentrations are elevated in obesity owing to large fat mass, and systemic leptin signaling is blunted despite high circulating leptin levels.
Therefore, exogenous leptin treatment results in no or minimal effects on body weight and neuroendocrine function Heymsfield et al. Similarly, leptin therapy only produces modest effects on insulin sensitivity in type 2 diabetes due to leptin resistance Mittendorfer et al.
Several in vivo experiments have explored the possible use of recombinant leptin or leptin antagonists in digestive organs. As discussed above, leptin augments proinflammatory responses and enhances susceptibility to autoimmune diseases, including UC La Cava et al. Indeed, Singh et al. Interestingly, they reported that PEG-MLA administration reduces systemic and mucosal inflammatory cytokine expression, thereby significantly attenuating the overall clinical features of colitis-associated pathogenesis.
However, treatment with leptin or leptin antagonists has not been actively examined in clinical settings, mainly because the underlying mechanisms of leptin action in the digestive system are still unclear. Furthermore, leptin action is multifunctional and complex, which modulates numerous signaling pathways thus increasing the likelihood of an adverse reaction.
Therefore, more information is needed regarding the molecular mechanisms of leptin in the digestive system to consider manipulation of leptin signaling in these tissues as a novel therapeutic approach. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been a subject of intensive research.
In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. Leptin Leptin is a hormone secreted from fat cells that helps to regulate body weight.
The name leptin is derived from the Greek word 'leptos' meaning thin. It is sometimes referred to as the 'Fat Controller'. Alternative names for leptin There are no other names used for the hormone but the gene , which encodes leptin, is known as the 'ob' gene.
What is leptin? How is leptin controlled? What happens if I have too much leptin? What happens if I have too little leptin? Last reviewed: Mar Prev. Luteinising hormone. Related Endocrine Conditions. Delayed puberty Diabetes mellitus Obesity View all Endocrine conditions. Related Hormones.
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