To determine the effects of food restriction and leptin administration on several transcripts involved in energy homeostasis, we examined leptin, uncoupling proteins (UCP) 1, 2 and 3, lipoprotein lipase (LPL), beta3-adrenergic receptors (beta3AR) and hormone-sensitive lipase (HSL) mRNA levels in brown adipose tissue (BAT) and epididymal (EWAT) and perirenal (PWAT) white adipose tissue in three groups of rats. The groups were administered leptin for 1 week, or had food restricted to the amount of food consumed by the leptin-treated animals, or had free access to food. Leptin administration increased serum leptin concentrations 50-fold and decreased food consumption by 43%, whereas serum insulin and corticosterone concentrations were unchanged. Leptin increased LPL mRNA by 80%, UCP1 mRNA twofold, and UCP3 mRNA levels by 62% in BAT, and increased UCP2 mRNA levels twofold in EWAT. In contrast, UCP2 mRNA levels were unchanged in PWAT and BAT. In WAT from food-restricted rats, leptin gene expression was diminished by 40% compared with those fed ad libitum. With leptin administration, there was a further 50% decrease in leptin expression. LPL mRNA levels were decreased by food restriction but not by leptin in WAT, whereas beta3AR and HSL mRNA levels were unchanged with either food restriction or leptin treatment. The present study indicates that leptin increases the gene expression of UCP2 in EWAT and that of UCP1, UCP3 and LPL in BAT, whereas reduced food consumption but not leptin, decreases LPL expression in WAT. In addition, with leptin administration there is a decrease in leptin gene expression in WAT, independent of food intake and serum insulin and corticosterone concentrations.

Abstract

Elevation of non-esterified fatty acids (NEFA) in vivo is associated with abnormal control of TSH. To determine whether TSH secretion is directly inhibited by NEFA, as has been reported for GH, cultured rat anterior pituitary cells were exposed for 20 h to oleic acid in medium containing 77 × 10⁻⁵ mol/l bovine serum albumin (BSA). In a molar ratio with albumin of 1·2 (total oleic acid 9× 1⁰ mol/l), or greater, oleic acid inhibited basal GH secretion (maximum inhibition to 40% of control) while basal TSH was less affected, a ratio of 3 (2·3 × 10⁻⁴ mol/l oleic acid) or greater causing a smaller degree of inhibition (maximum inhibition to 80% of control). In the presence of 10⁻⁹ mol/l growth hormone-releasing hormone or 10⁸ mol/l TRH, inhibition was achieved at a ratio of 12 (9 × 10⁻⁴ mol/l oleic acid) or greater. Basal TSH was less sensitive to inhibition by thyroxine (T₄) in the presence of oleic acid/albumin at a ratio of 6 or greater, and inhibition by oleic acid was less than additive with T₄ at a ratio of 6 or greater. Responses to tri-iodothyronine (T₃) were unaffected at a ratio of 6 (4·6 × 10⁻⁴ mol/l oleic acid), but a ratio of 12 inhibited the effects of both T₃ and T₄ on TSH. Oleic acid had less effect in the presence of TRH, a ratio of 12 causing a small increase in the threshold concentration of T₃ and T₄ for TSH inhibition. Further studies are required to determine the mechanism by which oleic acid inhibits the response of basal TSH to T₄ as well as the reason for a reduced effect of oleic acid in the presence of TRH. In some critically ill patients, total serum NEFA/albumin ratios from 1·5 to 6 have been reported, indicating that the direct inhibitory effects on TSH observed in vitro occur at free NEFA concentrations achieved in vivo. However, the direct inhibitory effect on TSH may be offset to some extent by reduced responsiveness to T₄ at higher oleic acid concentrations. Hence other sites of action of NEFA in vivo may also be important in limiting TSH secretion. Further studies should examine the hypothalamic hormones like TRH and somatostatin, which control the thyrotrophs, as potential sites of action of NEFA.

Journal of Endocrinology (1994) 143, 557–564