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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online April 22, 2003 as doi:10.1096/fj.02-0756fje. |
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Departments of Physiology and
* Obstetrics and Gynaecology, Adelaide University, SA 5005, Australia;
Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, UK;
Department of Animal Sciences, University of Missouri, Columbia, Missouri, USA; and
Department of Physiology, University of New England, Armidale NSW 2350, Australia
2Correspondence: Department of Physiology, Adelaide University, SA 5005, Australia. E-mail: caroline.mcmillen{at}adelaide.edu.au
SPECIFIC AIM
This study aimed to test the hypothesis that leptin acts before birth to regulate the lipid storage characteristics, leptin synthetic capacity, and potential thermogenic functions of fat before birth.
PRINCIPAL FINDINGS
1. Leptin infusion (0.48 mg·kg-1·day-1 i.v.) for 4 days into fetal sheep during late gestation resulted in a significant increase in the proportion of smaller lipid locules present within the unilocular component of fetal perirenal adipose tissue (PAT) (Fig. 1
)
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2. Administration of leptin resulted in a significant decrease in the proportion and relative mass of unilocular tissue in fetal PAT and in the relative abundance of leptin mRNA in fetal PAT
3. There was a positive correlation between relative abundance of leptin mRNA and the proportion of unilocular adipose tissue in fetal PAT (Fig. 2
)
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4. The proportion of multilocular tissue was higher and the amount of UCP1 protein tended to be higher (P=0.06) in leptin than with saline-infused fetuses
CONCLUSIONS AND SIGNIFICANCE
The role of leptin before birth
Leptin is synthesized in a range of uteroplacental and fetal tissues, including fetal adipose tissue; leptin concentrations in umbilical cord blood are positively correlated with birth weight and neonatal adiposity. It is unknown, however, whether leptin plays a role in the control of substrate utilization, maintenance of fat mass, or regulation of the expression of leptin or UCP1 in adipose tissue before birth.
Leptin and the regulation of leptin mRNA and UCP1 expression in fetal adipose tissue
Intrafetal infusion of leptin for 4 days from either 136 or 137 days gestation (term=147±3 days gestation) resulted in a four- to fivefold increase in circulating leptin levels and no change in fetal plasma glucose or insulin concentrations throughout the infusion period. Although leptin infusion did not result in a significant change in the total or relative fetal fat mass, it did result in a decrease in the proportion of unilocular adipose tissue. This decrease appeared to be a consequence of the shift toward smaller lipid locules in the unilocular tissue and an associated increase in the proportion of multilocular adipose tissue (Fig. 1)
. Ultrastructural studies have demonstrated that in fetal sheep, unilocular and multilocular adipocytes contain an abundance of mitochondria, a characteristic feature of the thermogenic brown adipocyte; though it is clear that leptin mRNA is expressed in fetal PAT, it is unknown whether leptin is expressed in unilocular or multilocular adipocytes. Leptin infusion decreased the relative abundance of leptin mRNA and there was a strong correlation between the proportion of unilocular fat and leptin mRNA expression in fetal PAT (Fig. 2)
. One possibility is that the unilocular adipocyte is a "transitional" cell type in fetal life that has lipid storage and leptin synthetic characteristics typical of the white adipocyte as well as thermogenic characteristics of the brown adipocyte. Recent studies, however, suggest that during normal development, most white adipocytes are not derived from brown adipocytes, and there are distinct lineages of white and brown adipocytes. An alternative explanation is that the unilocular and multilocular cells are brown adipocytes, but that leptin gene expression in these cells is stimulated when the size of the dominant lipid locule exceeds and then increases beyond a threshold value. This would explain the direct relationship between the relative abundance of leptin mRNA and the proportion of the PAT composed of unilocular tissue in the current study, as leptin infusion resulted in a shift in the size distribution of the lipid locules present in the unilocular tissue. There is evidence from studies in a range of species (including human, rat, and cow) that circulating leptin concentrations are related to the size of unilocular adipocytes, i.e., large fat cells are associated with higher circulating leptin concentrations. Independent of the cellular characteristics of unilocular and multilocular adipocytes, an increase in circulating leptin concentrations results in a decrease in the lipid storage capacity of unilocular adipose tissue and in the leptin synthetic capacity of PAT before birth.
Although leptin stimulated an increase in the multilocular component of PAT, it was not associated with an increase in UCP1 mRNA expression in fetal PAT, although UCP1 protein levels tended to be higher (P=0.06) in the leptin-infused group than controls. One possibility is that UCP1 mRNA is expressed in both the mitochondrial replete unilocular and multilocular tissue in the fetus but that UCP1 protein levels are higher in those adipocytes in which lipolytic activity is increased by leptin infusion, i.e., those unilocular cells that have smaller lipid locules and the multilocular cells.
Mechanisms of action of leptin in the fetus
In the adult, activation of the sympathetic nervous system is required for the effects of leptin on leptin and UCP1 gene expression in white and brown adipose tissue, respectively. In the sheep, sympathetic innervation in perirenal adipose tissue occurs at 
130 days gestation, and there is an increase in the proliferation of sympathetic nerves within this tissue from 140 days gestation up to term. One possibility is that leptin acts centrally via leptin receptors located within the fetal hypothalamus to stimulate the sympathetic nervous system resulting in a decrease in the proportion of the unilocular adipose tissue, in the abundance of leptin mRNA, and a concomitant increase in the proportion of the multilocular or thermogenic component of the PAT (Fig. 3
).
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Though leptin may exert its actions centrally, it is also possible that leptin acts directly via leptin receptors on the unilocular and multilocular adipocytes to stimulate lipolysis and a shift in the distribution of the lipid locule sizes. Even though it has been demonstrated that leptin can directly stimulate lipolysis in isolated adipocytes, some studies have failed to demonstrate local effects of leptin in adipocytes from a range of species, including humans and sheep.
Leptin and fetal growth
We found no evidence for an effect of increased circulating leptin concentrations on fetal body or organ growth during the 4 day infusion period. In the sheep, increases in leptin mRNA expression in fetal PAT and circulating leptin concentrations occur during periods of rapid fetal growth in late gestation; in humans there are relationships between circulating leptin and measures of fetal size or neonatal weight. These relationships may be determined by the effect of the prenatal nutrient supply on fetal growth, adiposity, and leptin synthesis and secretion rather than reflecting the actions of circulating leptin on prenatal growth.
In summary, this is the first demonstration that leptin can act to regulate the lipid storage characteristics, leptin synthetic capacity, and potential thermogenic functions of fat before birth. These findings suggest that leptin may act as a signal of energy supply and have a "lipostatic" role before birth. This role may be particularly important when the fetus is exposed to an increase in a transplacental increase in substrate supply such as occurs when maternal nutrient intake is increased or in pregnancies complicated by maternal glucose intolerance and fetal hyperglycemia. Studies are needed to determine the central and peripheral sites and mechanisms of action of leptin and the postnatal consequences of prenatal hyperleptinemia.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0756fje; to cite this article, use FASEB J. (April 22, 2003) 10.1096/fj.02-0756fje 
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