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Leptin plays an important role in regulating energy expenditure in response to food intake, but nutrient regulation of leptin is incompletely understood. In this study using in vivo and in vitro approaches, we examined the role of fatty acid uptake in modulating leptin expression and production. Leptin levels are doubled in the CD36-null mouse, which has impaired cellular fatty acid uptake despite a 40% decrease in fat mass. The CD36-null mouse is protected from diet-induced weight gain but not from that consequent to leptin deficiency. Leptin secretion in the CD36-null mouse is strongly responsive to glucose intake, whereas a blunted response is observed in the wild-type mouse. This indicates that leptin regulation integrates opposing influences from glucose and fatty acid and loss of fatty acid inhibition allows unsuppressed stimulation by glucose/insulin. Fatty acid inhibition of basal and insulin-stimulated leptin release is linked to CD36-facilitated fatty acid flux, which is important for fatty acid activation of peroxisome proliferator-activated receptor gamma and likely contributes to the nutrient sensing function of adipocytes. Fatty acid uptake also may modulate adipocyte leptin signaling. The ratio of phosphorylated to unphosphorylated signal transducer and activator of transcription 3, an index of leptin activity, is increased in CD36-null fat tissue disproportionately to leptin levels. In addition, expression of leptin-sensitive fatty acid oxidative enzymes is enhanced. Targeting adipocyte CD36 may offer a way to uncouple leptin production and adiposity.

Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis. DGAT1-deficient mice are resistant to diet-induced obesity through a mechanism involving increased energy expenditure. Here we show that these mice have decreased levels of tissue triglycerides, as well as increased sensitivity to insulin and to leptin. Importantly, DGAT1 deficiency protects against insulin resistance and obesity in agouti yellow mice, a model of severe leptin resistance. In contrast, DGAT1 deficiency did not affect energy and glucose metabolism in leptin-deficient (ob/ob) mice, possibly due in part to a compensatory upregulation of DGAT2 expression in the absence of leptin. Our results suggest that inhibition of DGAT1 may be useful in treating insulin resistance and leptin resistance in human obesity.

Abstract: Rodent experiments raise the possibility of a regulatory role of peripheral α–melanocyte-stimulating hormone (α-MSH) in obesity and metabolism, but human data on peripheral α-MSH levels remain fragmentary. Because of the possible relationship between α-MSH and obesity, we endeavored to test the hypothesis that higher levels of α-MSH in obese patients would correlate with leptin levels and with other markers of obesity. Sixty normal-weight to obese healthy men and women participated. Weight, measures of body composition, and diet diaries were obtained; fasting blood was analyzed for α-MSH, lipids, glucose, insulin, leptin, and adiponectin. To begin to understand the source of peripherally measured hormones, α-MSH was also measured in serum samples from 5 individuals with untreated Addison disease. Levels of α-MSH were higher in men vs women (10.1 ± 4.3 vs 7.6 ± 3.4 pmol/L, P = .019), and α-MSH levels were higher in patients with Addison disease vs controls (17.7 ± 2.3 vs 8.7 ± 0.52 pmol/L, P < .001). Measures of adiposity correlated with insulin and leptin in men and women, and with adiponectin in women. α–Melanocyte-stimulating hormone levels did not correlate significantly with any parameter of adiposity or diet composition. The elevated α-MSH levels in patients with untreated Addison disease suggest possible pituitary secretion of α-MSH to the periphery. The lack of correlation between peripheral α-MSH and parameters of adiposity suggests that endogenous plasma α-MSH levels are not a metric for body composition per se. [Copyright &y& Elsevier]

Reveals that inhibition of diacylglycerol acyltransferase 1 (DGAT1) may be useful in treating insulin resistance and leptin resistance in human obesity. Information on the tissue lipid analysis; Effects of DGAT1 deficiency on energy and glucose metabolism in Agouti yellow and leptin-deficient mice.