Obesity leptin

Currently in development Leptin Obesity. Obesity, hypothalamic amenorrhea... 

Leptin has proved to be an efficient treatment for the rare form of obesity associated with leptin deficiency. By contrast, the results of the fust clinical trial with human leptin in obese patients (without leptin deficiency) were less promising. This may be explained by leptin resistance in a high proportion of these patients. However, the mechanisms involved in the development of leptin resistance could become new drug targets. 

Leptin is a cytokine produced and secreted by adipose tissue in proportion to the body fat content [3]. Mice and humans lacking leptin or its receptor develop a severe hyperphagia and a dramatic degree of obesity which is considerably more pronounced than that of the NDRKO mouse. Thus, leptin is the key adiposity signal in rodents and humans. Leptin secretion appears to reflect the metabolic status of the adipocyte rather than the sheer size of triglyceride deposits, and leptin levels may transiently be dissociated from total body fat. Nonetheless, over the course of a day with unrestricted food supply, plasma leptin levels reliably reflect the amount of total body fat. Local administration of leptin into the brain results in reduced food intake. The vast majority of patients with obesity have elevated serum levels of leptin. Thus, it is believed that the polygenic obesity is due to leptin resistance rather than to inadequate leptin secretion, or to a reduced blood/brain transport of the cytokine. 

Leptin has been shown to markedly reduce appetite and weight in the extremely rare individuals who lack leptin. In contrast, in the first clinical study of patients with polygenic obesity and elevated leptin levels, weight loss was variable and relatively small. This disappointing result may be explained by the leptin resistance consistently observed in obese humans and rodents. However, it cannot be excluded that a small... 

In addition to fiber and carbohydrate content, protein intake from legumes may have weight-loss benefits for obese individuals just because proteins enhance post-meal satiety (Rolls, 1995). However, a possible specific role for phytoestrogens in obesity has been postulated through the modulation of the satiety response, a neuroendocrine mechanism controlled by leptin (a hormone secreted by adipose tissue and already known to be regulated by... 

Poor sleep architecture and fragmented sleep secondary to OSA can cause excessive daytime sleepiness (EDS) and neu-rocognitive deficits. These sequelae can affect quality of life and work performance and may be linked to occupational and motor vehicle accidents. OSA is also associated with systemic disease such as hypertension, heart failure, and stroke.21-23 OSA is likely an independent risk factor for the development of hypertension.24 Further, when hypertension is present, it is often resistant to antihypertensive therapy. Fatal and non-fatal cardiovascular events are two- to threefold higher in male patients with severe OSA.25 OSA is associated with or aggravates biomarkers for cardiovascular disease, including C-reactive protein and leptin.26,27 Patients with sleep apnea often are obese and maybe predisposed to weight gain. Hence, obesity may further contribute to cardiovascular disease in this patient population. 

High-fat diet studies with DGATl-/- and DGATl+/- mice demonstrated that the absence of DGAT1 activity may lead to increased insulin sensitivity, leptin sensitivity, protection against diet-induced obesity, and protection against liver steatosis [40-43]. 

Axokine affects the leptin pathway in the brain. As discussed in Chapter 2, leptin is a chemical messenger that tells the brain when the body has had enough to eat. People who are obese may not respond appropriately to this messenger, thus they may not realize they are full. Axokine apparently helps these individuals respond appropriately to leptin. 

Neuropeptides play key roles in appetite regulation and obesity. Many genes for neuropeptides and neuropeptide receptors have been implicated in obesity and cachexia, anorexia and bulimia [34]. For example,NPY administration into the CNS causes overeating and obesity. A second peptide involved in obesity is leptin, a product of adipocytes and the stomach. The leptin gene is defective in the ob/ob mouse but in normal mice leptin binds to its receptor in the hypothalamus, causing a decrease in the synthesis and release of hypothalamic NPY. 

Obesity is associated with higher circulating concentrations of leptin that would be found in non-obese individuals. Although this effect can be explained by expansion of adipose tissue mass, there is reason to believe that obesity may also be due to leptin insensitivity in the target tissues. 

Fig. 12.1 Leptin-deficient (ob/ob) mouse. (From http //www.obesity-news.eom/abs01-00.htm.)...

Montague, C. T., Farooqi, I. S., Whitehead, J. P., et al. (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 387, 903-908. 

One of the classical obesity mntations in mice is termed ob, for obesity. Mice that are homozygous for the ob mutation (ob/ob mice) are grossly obese. Jeffrey Friedman at the Rockefeller University elucidated the defect in ob/ob mice in 1992. Specifically, the ob gene encodes a protein termed leptin.Leptin is prodnced in fat tissue and acts on the central nervous system at the hypothalamus. Basically, it reports nutritional information to this control center. 

Leptin is a homeostatic hormone. It inhibits food intake and promotes energy expenditnre. Therefore, in the face of a loss in body fat, the levels of leptin decrease and food intake is stimnlated. In contrast, if body fat stores increase, the levels of leptin increase as well and food intake is decreased and energy expenditure increased. Therefore, leptin tends to maintain body weight within fairly close limits. Since ob/ob mice are genetically deficient in leptin, it follows that administration of leptin shonld tend to restore normal body weight. That is exactly what happens. Injection of leptin into ob/ob mice reduces their food intake dramatically and they tend toward the body weights of their normal littermates. In these mice at least, leptin is a powerful force for treatment of obesity. 

The leptin story has been augmented by a second mouse genetic defect leading to obesity. These mice are known as db/db they are very similar to ob/ob mice. However, these mice have normal levels of leptin. Scientists at Millennium Pharmaceuticals identified the molecular defect in db/db mice. They lack the normal leptin receptor. Therefore, we have both sides of the coin ob/ob mice cannot make leptin, eat too much, and are therefore obese db/db mice make leptin, cannot respond to it for lack of the leptin receptor, eat too much, and are obese. Administration of leptin to ob/ob mice normalizes their body weight but administration of leptin to db/db mice has... 

The results with ob/ob mice stimulated enormous interest in the potential use of leptin for the treatment of hnman obesity. Amgen, a prominent biotechnology company, gained the rights to develop leptin for hnman use. hi fact, it is known that hnman mutations leading to leptin deficiency are associated with massive obesity in hnmans. However, these mntations are very rare and acconnt for a minute part of the human obesity problem. 

I have already mentioned leptin. There are several others, notably including adiponectin, a protein present in high concentrations in blood. Adiponectin is an antihyperglycemic agent, acting to increase insulin sensitivity. There is a close relationship between obesity, insulin action, and development of type 2 diabetes. Withont listing additional peptides secreted by adipose tissue, it is important to understand that fat is an important player in human physiology. 

Schmidt 1, Fritz A, Scholch C, Schneider D, Simon E, Plagemann A (2001) The effect of leptin treatment on the development of obesity in overfed suckling Wistar rats. Int J Obes 25 1168-1174... 

Recent studies of H3-receptor knockout mice demonstrate that absence of this receptor results in animals with increased food intake, decreased energy expenditure, and obesity. They also show insulin resistance and increased blood levels of leptin and insulin. It is not yet known whether the H3 receptor has a similar role in humans, but intensive research is underway to determine whether H3 agonists can be used in the treatment of obesity. 

Leptin Lipid status messenger, doesn t work as obesity drug due to leptin resistance in obese people... 

---