Determinants of Fetal Leptin Synthesis, Fat Mass, and Circulating Leptin Concentrations in Well-Nourished Ewes in Late Pregnancy

Abstract

We have investigated the factors regulating leptin synthesis, fat deposition, and circulating leptin concentrations in fetuses of well nourished ewes in late pregnancy. Vascular catheters were surgically inserted in 17 pregnant ewes and their fetuses at 103-120 d gestation (term = 147 +/- 3 d). Ewes were fed a diet providing either 100% (control; n = 9) or approximately 155% (well fed; n = 8) of the maintenance energy requirements and fetal perirenal and interscapular fat depots were collected at 139-141 d gestation. There was a significant relationship between the relative mass of fetal unilocular fat and fetal glucose (relative mass of unilocular fat, 1.14; fetal glucose, +0.16; r = 0.50; P < 0.04; n = 17), but not insulin, concentrations in the control and well-fed groups. In contrast to the controls, there was a positive relationship between the relative abundance of leptin mRNA and fetal insulin, but not glucose, concentrations in fetal perirenal adipose tissue in the well-fed group. A moderate increase in maternal nutrition also resulted in a strong reciprocal relationship between uncoupling protein 1 and leptin expression in fetal perirenal adipose tissue in late gestation (well-fed group: uncoupling protein 1 mRNA:18S rRNA, -0.51; leptin mRNA:beta-actin mRNA, +1.53; r = 0.80; P < 0.02; n = 8). These studies provide evidence that fetal glucose and insulin differentially regulate fetal fat deposition and leptin mRNA expression within the fetal perirenal fat depot in the well nourished animal during late gestation.

Regulation of leptin synthesis and secretion before birth: implications for the early programming of adult obesity

“…The mean lipid locule size was also directly related to fetal glucose, but not insulin, concentrations during the infusion period in the saline-and the glucose-infused fetuses. This is consistent with the finding of a similar relationship between glucose concentrations and lipid locule size in the fetal adipose tissue of the well-nourished ewe (Muhlhausler et al 2003), and suggests that glucose, rather than insulin, is the principal determinant of lipid storage in fetal adipocytes during late gestation. This is supported by previous reports that the abundance of the insulin-independent glucose transporter (GLUT1) is greater than that of the insulindependent glucose transporter (GLUT4) in the adipose tissue of the sheep fetus in late gestation (Das et al 1998).…”

“…In these well-nourished ewes there was, however, a significant relationship between fetal glucose and the relative mass of fetal unilocular fat, and a positive relationship between fetal insulin concentrations and the relative abundance of leptin mRNA in fetal perirenal adipose tissue (Muhlhausler et al 2003). Insulin-responsive elements have been identified within the promoter of the leptin gene in the adult mouse and insulin upregulates leptin gene transcription in adipocytes of adult rodents (Saladin et al 1995).…”

“…Intrafetal leptin infusion, resulting in a 4-to 5-fold increase in circulating leptin concentrations suppressed the normal prepartum increase in fetal cortisol concentrations for an extended period from 90 to 42 h before delivery but did not alter the timing of parturition in these animals (Yuen et al 2004). Intrafetal leptin infusion in the presence of normoglycaemia and normoinsulinaemia also results in an increase in the proportion of multilocular tissue and a decrease in the proportion and relative mass of unilocular tissue in the perirenal adipose depot; the relative abundance of leptin mRNA in perirenal adipose tissue was also lower in leptin-infused fetuses and, in addition, there was a strong correlation between the proportion of unilocular fat and leptin mRNA expression in this tissue (Yuen et al 2003). These findings suggest that leptin may act as a signal of energy supply and have a 'lipostatic' role before birth (Fig.…”

“…Interpretation of differences in baseline plasma leptin concentrations in ruminants is also complicated to some extent by the use of different assays, which appear to provide different values for leptin in animals in the same body weight and body condition range (Chilliard et al 2001). Ultrastructural studies of adipose tissue in the sheep fetus have demonstrated that fetal adipocytes contain multiple lipid locules and an abundance of mitochondria, and express uncoupling protein 1 (UCP1): characteristic features of thermogenic or brown adipose tissue (Gemmell et al 1972, Gemmell & Alexander 1978, Symonds & Stephenson 1999, Yuen et al 2003. Fetal adipocytes also contain larger or dominant lipid locules and there is a direct relationship between the relative mass of the 'unilocular' component of perirenal and interscapular fat, and circulating leptin concentrations in a cohort of fetuses in well-nourished pregnant ewes (Muhlhausler et al 2002).…”

Endocrine and nutritional regulation of fetal adipose tissue development

“…Despite the relatively small amount of adipose tissue present in the fetus, its growth is under marked nutritional constraints. In contrast to many other fetal organs that are unaffected by nutritional manipulation, fat mass can be significantly altered by changes in maternal and, therefore, fetal nutrition (Budge et al 2003). The present review will therefore consider the following critical aspects of fetal adipose tissue development:…”