Leptin and Its Role in Obesity
In the past few decades, obesity has reached paramount proportions in western society. Obesity is linked to an increased risk for developing cardiovascular disease, hypertension, and diabetes mellitus (Type II diabetes). Leptin is an adipocyte-derived hormone that functions in a negative feedback loop that sends information on peripheral energy stores to the hypothalamus allowing alterations in food intake and metabolic rate.
Differences in leptin production or leptin sensitivity could contribute to differences in weight among various individuals. Under normal physiological circumstances, when fat stores are sufficient, leptin suppresses appetite and increases metabolic rate. Circulating leptin levels are regulated by energy balance and can be considered to be indicative of the fat stores of a given organism. Food deprivation decreases fat stores causing a decrease in leptin levels in the bloodstream, as well as marked changes in metabolism and other hormonal signaling mechanisms. Food consumption restores these levels to an acceptable physiological range.
Much of the research regarding leptin and its physiological pathways has used mice lacking the Obese (Ob) gene which produces leptin. The leptin-deficient ob/ob mice are obese with approximately 30% more body fat than their wild-type counterparts. Treatment of ob/ob mice with low doses of leptin results in dramatic weight loss. Leptin treatments are also beneficial in reducing weight in genetically normal mice that were obese due only to overeating. These findings were supported by multiple studies and stimulated interest regarding the possibility of using leptin replacement therapy as a treatment for human obesity (Ioffe et al. 1998, Xiong et al. 2004).
Unfortunately, the relationship between leptin levels and obesity in humans is not straightforward. Rather than being leptin-deficient, many overweight individuals appear to have adequate amounts of leptin. Leptin levels appear to increase, rather than decrease, with an increase in the body’s fat stores. Recent research has demonstrated that only a small subset of overweight and obese individuals do not produce enough leptin or are insensitive to the effects of the hormone. In these patients, it is possible that a progressively decreasing rate of leptin production by adipose tissue led to the addition of unnecessary fat stores. Other lines of evidence suggest that obesity is related to deficient leptin receptors, rather than inadequate amounts of leptin being produced. The leptin molecules are unable to bind to their receptors. In such situations, leptin replacement therapy would not help increase weight loss or prevent weight gain.
A successful treatment approach to the obesity epidemic would include a treatment that allows weight loss and decreases the possibility for rebound weight gain. Overeating, high-fat diets, and physical inactivity are cultural factors that promote weight gain in the population. In order to halt the ever-increasing percent of Americans who are overweight or obese, individuals must be able to make informed decisions about lifestyle habits. Aside from awareness and access to healthy foods, people must possess the determination to lose weight and prevent rebound weight gain. Changing the cultural environment to encourage behaviors that prevent obesity may seem insurmountable, but an increase in public health education can be of assistance. In regards to obese patients with a deficiency in leptin or those that may be leptin-resistant, advancements in hormonal therapy, as well as a healthy lifestyle, may help decrease the risk of developing other obesity-related health complications.
Ioffe E, Moon B, Connolly E, Friendman JM. Abnormal regulation of the leptin gene in the pathogenesis of obesity. (1998). Proc. Natl. Acad. Sci. USA, 95: 11852-11857.
Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M. Short-chain fatty acids stimulate leptin production adipocytes through the G protein- coupled receptor GPR41. (2004) Proc. Natl. Acad. Sci. USA, 101(4): 1045-1050.