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.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology