ESPE Abstracts (2019) 92 FC15.6

Leptin Influences the Down-Regulation of UCP-1 Expression in Brown Adipose Tissue During Negative Energy Balance

Vicente Barrios1,2, Sandra Canelles1,2, Laura M. Frago1,2,3, Julie A. Chowen1,2,3,4, Jesús Argente1,2,3,4


1Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain. 2CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain. 3Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain. 4IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain


Background: The GH/IGF-I axis is involved in metabolic control and studies suggest that IGF-I deficiency and subsequent changes in IGF-I signaling in brown adipose tissue (BAT) modifies its thermogenic capacity. Food restriction reduces thermogenic capacity in BAT, while leptin stimulates thermogenesis through uncoupling protein 1 (UCP-1) induction. Leptin and IGF-I maintain important crosstalk in different tissues, but whether these two hormones interact to regulate thermogenesis in BAT remains unknown.

Objectives: We compared the effect of chronic central leptin infusion, which reduces food intake resulting in weight loss but with high central and circulating leptin levels, with pair-fed animals that have reduced bodyweight with normal leptin levels, on the GH/IGF-I axis and the activation of IGF-I-related signaling and metabolism related to BAT thermogenesis.

Methods: Eighteen male Wistar rats were divided into control (C), icv leptin infusion (12 µg/day) for 14 days (L) and pair-fed (PF) groups. The mRNA levels of hypothalamic somatostatin, pituitary GH and BAT UCP-1 and UCP-2 were studied by real-time PCR. Serum GH and IGF-I levels and activation of IGF-I receptor (IGF-IR) in BAT were determined by ELISA, association between suppressor of cytokine signaling 3 (SOCS-3) and IGF-IR by immunoprecipitation and glucose transporter 4 (Glut4) levels in BAT by Western blotting. Hepatic activation of signal transducer and activator of transcription 5 (STAT5) and phosphorylation of STAT3, Akt and cyclic AMP response element binding protein (CREB) in BAT were analyzed by multiplexed bead immunoassay.

Results: Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L rats. Pituitary GH mRNA levels were reduced in PF rats, as were serum GH and IGF-I concentrations and hepatic STAT5 activation, suggesting that a forced reduction in food intake suppresses the systemic GH/IGF-I axis, while the reduction in food intake as a result of leptin infusion does not. In contrast, in BAT the phosphorylation of STAT3 and the association between SOCS3 and IGF-IR were reduced and phosphorylation of IGF-IR, Akt and CREB increased, as well as Glut4 levels in the L group, suggesting that IGF-I signaling is increased, as well as possibly glucose transport. UCP-1 mRNA levels were reduced in PF rats, with no changes in UCP-2 mRNA levels.

Conclusions: BAT metabolism and thermogenesis are differentially affected by a reduction in food intake depending on the hormonal environment. Our results suggest that the differential response of BAT could be related to an interaction between leptin- and IGF-I-related signaling.

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