In comparison with the on leptin period, we show in the off-leptin period shows that several changes in macronutrient intake occur: The ingestion of total fat decreased by 17.6%, the intake of carbohydrates decreased by 27.5%, and protein intake decreased by 28.5%. The overall proportion of fat, carbohydrate and protein in the daily diet did not change in the off-leptin state (see ). Additionally, we report that off leptin there were statistically significant decreases in the intake of the specific micronutrients: Vitamin C, pyridoxine, pantothenic acid, folate, potassium, magnesium, copper, chromium, threonine, lysine, histidine, tryptophan, methionine and cystine (see –).
Various studies have shown that the extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, which is an adipocyte-specific secreted protein with profound effects on appetite and energy expenditure. Clinical research studies of leptin gene mutations have demonstrated severe obesity in congenital leptin-deficiency, which is reversed with leptin treatment (Farooqi et al., 1999
; Farooqi et al., 2002
; Licinio et al., 2004
; Montague et al., 1997
). These findings support the conclusion that leptin is an important regulator of energy balance in humans.
In a four year study of congenitally deficient, morbidly obese children treated with daily dose of recombinant human leptin, there was compelling evidence that the subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency. This included beneficial effects on appetite, fat mass, hyperinsulinemia, hyperlipidemia, plasma thyroid hormone levels, cytokine production and release, circulating CD4(+) T cells and T cell proliferation (Farooqi et al., 1999
; Farooqi et al., 2002
In a recent study, we reported the effects of leptin therapy in three leptin deficient adults, including the one reported here (Williamson et al., 2005
). There were key differences between that study and the data presented here. First, that study provided a microanalysis of changes in eating behavior and rating of hunger and satiety, but macro- and micro-nutrient intake was not examined. Importantly, that study was conducted during the onset of leptin treatment when subjects were morbidly obese and losing weight, while we report the effects of withdrawal of leptin after the subject was stable at a normal weight.
In conclusion, we report that even brief discontinuation of leptin therapy results in marked loss of weight and significant changes in micro- and macro-nutrient intake. This is to our knowledge the first report of the specific effects of leptin on micronutrient intake in humans. The implications of these results are several-fold. Because our leptin-deficient subject has been maintained at a very low doses of leptin (0.2 mg/day), it had been unclear if continuous leptin treatment is required. The data presented here indicate that even a short leptin-free period profoundly affects food intake and nutrient ingestion in leptin-deficient patients. Therefore, long-term, and possibly lifelong, replacement treatment will be required. On the other hand, we show that in the context of a well-supervised research inpatient setting, it is possible to conduct studies that compare and contrast at a normal to mildly overweight range of body weight the off and on leptin states. This opens up a new avenue for research on the effects of human leptin. Such studies are made possible by these rare but highly informative cases of leptin deficiency.
Previous reports of leptin-deficiency have been restricted mostly to children who are still in a growth phase. These studies have not included detailed data on the nutritional effects of withdrawing leptin treatment in the context of normal and chronically stable body weight. The fact that our patient was an adult with stable weight in response to a fixed low dose regimen of leptin replacement gives us the unique opportunity to ascertain the effects of leptin on nutrition by comparing data from the treated (on) and the non-treated (off) states.
Our results provide further support for the hypothesis that the human leptin pathway is crucial for the regulation of food intake and body weight, and that non-monogenic types of obesity are characterized by a state of leptin resistance. Pharmacological attempts to overcome leptin resistance (Wang, Orci, Ravazzola, & Unger, 2005
) may have a promise in the experimental treatment of obesity in the future.