Leptin resistance

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... 

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

Correia ML, Haynes WG. Obesity-related hypertension Is there a role for selective leptin resistance Curr. Hypertens. Rep. 2004 6 230-235. 

Hintz, K. K., Aberle, N. S., and Ren, J. 2003. Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes. Int. J. Obes. Relat. Metab. Disord. 27 1196-1203. 

Munzberg, H., and Myers, M. G., Ir. 2005. Molecular and anatomical determinants of central leptin resistance. Nat. Neurosci. 8 566-570. 

J. F. Caro, J. W. Kolaczyn.ski, M. R. Nyce, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity A possible mechanism for leptin resistance. Lancet 348, 159(1996). 

Lin, S., Thomas, T.C., Storlien, L.H. and Huang, X.E (2000) Development of high fat diet-induced obesity and leptin resistance in C57B1/6J mice, Int J Obes Relat Metab Disord, 24 639-46. 

Martin SS, Qasim A, Reilly MP. Leptin resistance a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. ] Am College Cardiol. 2008 52(15) 1201-1210. 

The relationships between valproate-induced obesity in children and concomitant metabolic changes, such as hyper-insulinemia and insulin resistance, h)q)erleptmemia and leptin resistance, and an increase in the availability of long-chain free fatty acids, have been reviewed [371 ]. The authors concluded that, although mechanisms of hyperinsulinemia in valproate-induced weight gain are unclear, it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. 

The effects of leptin on adipocyte and liver metabolism in leptin-responsive and leptin-resistant rats... 

In Experiment 2,18 male Wistar 230 g rats were fed either a LF (12% kcal fat D02041902 Research Diets) or a HF diet (60% kcal fat D12492 Research Diets). Leptin responsiveness was tested by measuring 12 hour food intake following an i.p. injection of 2.5 mg/kg leptin. Leptin inhibited 12 hour food intake of both LF and HF-fed rats at 5 and 9 weeks, but after 11 weeks leptin resistance was confirmed in HF-fed rats. Daily food intakes and body weights were then measured for 4 days before the rats were fitted with i.p. Alzet pumps that delivered either 70 pg leptin/day or an equal volume of PBS. On day 2 the rats were moved to the indirect calorimeters and data were collected from the last three days. On day 11 the rats were killed and measures of serum metabolites and EPI adipocytes and liver metabolism were made. 

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