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CD36-Facilitated Fatty Acid Uptake Inhibits Leptin Production and Signaling in Adipose Tissue

¹ Department of Surgery, Vanderbilt University, Nashville, Tennessee
² Division of Nutritional Sciences, Department of Medicine, Washington University, St. Louis, Missouri
³ Division of Endocrinology, University of Colorado Health Sciences Center, Aurora, Colorado
⁴ Department of Pharmacology, Stony Brook University, New York

Address correspondence and reprint requests to Nada A. Abumrad, PhD, Department of Medicine, Division of Nutritional Sciences, Campus Box 8031, Washington University, St. Louis, MO 63110. E-mail: nabumrad{at}wustl.edu

Abbreviations: ACO, acyl-CoA oxidase; CPT1, carnitine palmitoyl transferase 1; Ct, threshold crossing of each sample after normalization; PPAR, peroxisome proliferator–activated receptor ; p-STAT3, signal transducer and activator of transcription 3 phosphorylation; STAT3, signal transducer and activator of transcription 3; UCP2,uncoupling protein 2

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 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.

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