Leptin is a peptide hormone that is produced in adipocytes. The circulating levels of leptin are proportional to the amount of body fat. Circulating leptin levels therefore increase in obese individuals, as blood leptin levels rise concomitantly with adiposity. Leptin is an afferent signal for the hypothalamus, that informs the brain of the degree of body fat. In response to high circulating levels, the hypothalamus initiates countermeasures to lower body fat. These include decreased energy intake through a reduced appetite as well as increased energy expenditure, through thermogenic stimulation and increased physical activity. However, obese individuals may develop leptin resistance in the hypothalamus, and therefore the hypothalamus perceives low levels of leptin, when actually they are high. As a result no countermeasures are initiated in response to weight gain. This disengagement between circulating leptin and the hypothalamic responses to body fat gain and loss has been observed in obese subjects.
Researchers have analysed the leptin levels of obese subjects during periods of dieting, For example, in one study1, obese subjects consumed a low energy diet for 10 weeks and then consumed a weight maintenance diet for approximately 1 year. During this time the circulating levels of leptin were measured. During the 10 week diet period, when the subjects lost a significant amount of weight (presumably including body fat and muscle, although the authors did not measure the percentage fat, only weight) the leptin levels of the subjects decreased significantly. However, as weight was regained in the proceeding year, the leptin levels increased in proportion to the regained weight. At the completion of the study, the leptin levels had not returned to baseline levels, but were still depressed somewhat. The leptin levels of the subjects therefore mirrored the loss and gain of body fat. However, the appetite of the subjects increased as leptin levels increased, suggesting that the hypothalamus was resistant to the leptin signal.
One of the functions of leptin is to signal the initiation of satiety signals in the central nervous system in response to increases in body fat. The observation that obese subjects gaining weight experienced increased rather than decreased appetite supports the contention that these subjects were leptin resistant and that their leptin signal was not performing its normal physiological role. Such leptin resistance is rarely considered when considering weight loss regimens, and this is unfortunate because without addressing the underlying leptin resistance, any weight loss strategy is doomed to failure in the long term. One hypothesis that is supported by experimental data is that leptin resistance develops secondary to insulin resistance. Insulin resistance therefore appears to be the underlying physiological change that leads to weight gain and metabolic dysfunction, and should be the first area addressed if meaningful fat loss is to be achieved. High quality diets have been shown to reverse insulin resistance in humans.
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1Sumithran, P., Prendergast, L. A., Delbridge, E., Purcell, K., Shulkes, A., Kriketos, A. and Proietto, J. 2011. Long-term persistence of hormonal adaptations to weight loss. The New England Journal of Medicine. 365: 1597-1604
