Sophie Turban

Angiotensinogen-Deficient Mice Exhibit Impairment of Diet-Induced Weight Gain with Alteration in Adipose Tissue Development and Increased Locomotor Activity

White adipose tissue is known to contain the components of the renin-angiotensin system, which gives rise to angiotensin II from angiotensinogen (AGT). Recent evidence obtained in vitro and ex vivo is in favor of angiotensin II acting as a trophic factor of adipose tissue development. To determine whether AGT plays a role in vivo in this process, comparative studies were performed in AGT-deficient (agt−/−) mice and control wild-type mice. The results showed that agt−/− mice gain less weight than wild-type mice in response to a chow or high fat diet. Adipose tissue mass from weaning to adulthood appeared altered rather specifically, as both the size and the weight of other organs were almost unchanged. Food intake was similar for both genotypes, suggesting a decreased metabolic efficiency in agt−/− mice. Consistent with this hypothesis, cellularity measurement indicated hypotrophy of adipocytes in agt−/− mice with a parallel decrease in the fatty acid synthase activity. Moreover, AGT-deficient mice exhibit...

Transcriptional effect of hypoxia on placental leptin.

We observed recently1 that placental leptin is markedly increased in preeclampsia. Since this disorder is associated with vascular disorders, we have tested the hypothesis that hypoxia regulates leptin expression. We show that hypoxia increased leptin mRNA and secretion in trophoblast‐derived BeWo cells. This effect was mediated through leptin promoter activation. 5′ deletion analysis allowed us to delineate two regions containing 1.87 kb and 1.20 kb of the promoter which conferred respectively high and low responsiveness to hypoxia. These data indicate that leptin is up‐regulated by hypoxia through a transcriptional mechanism likely to involve distinct hypoxia‐responsive cis‐acting sequences on the promoter.

Specific increase in leptin production in obese (falfa) rat adipose cells

In the obese state, enlarged adipose cells display an altered gene-expression profile and metabolic capacity. The aim of this study was to gain insight into their secretory function, by assessing two secreted proteins, leptin and angiotensinogen, in adipose cells of obese (fa/fa) Zucker rats. A marked and co-ordinate increase in leptin mRNA, gene transcription and promoter activity was observed in obese compared with lean (Fa/fa) rat adipose cells, and this resulted in increased leptin release in culture. Two sets of observations suggest that this effect is due to the fa mutation. First, adipose-cell leptin release was higher in heterozygous (Fa/fa) than in homozygous (Fa/Fa) lean rats. Second, leptin release was not enhanced in enlarged adipose cells of FalFa rats fed a high-fat diet for 15 days. At variance with leptin, angiotensinogen production was not significantly increased in the obese cells. Dexamethasone stimulated both leptin and angiotensinogen release in lean and obese rat adipose cells. The magnitude of leptin stimulation was higher in fa/fa than in Fa/fa rats, whereas angiotensinogen release was increased to the same extent in both genotypes. These observations suggest that leptin production is specifically enhanced in enlarged adipose cells of obese Zucker rats and that cell hypertrophy is not the sole determinant of this feature. Increased leptin production might be related to disruption of leptin signalling by the fa mutation.

Molecular and cellular mechanisms of adipose secretion: Comparison of leptin and angiotensinogen

Besides their function of lipid storage, the adipose cells secrete a number of proteins of physiopathological importance. To get further insights into this function, which remains poorly characterized, we sought to compare the mechanisms and regulation of secretion of two individual proteins in the same cells. Leptin and angiotensinogen were chosen and assessed by radioimmunoassay and quantitative immunoblotting, respectively, in primary culture of epididymal adipose cells from young obese Zucker rats. Leptin was secreted at a steady rate of 4 ng/106 cells/h over 2–6 h. Despite secretion, leptin cellular content remained stable at 3 ng/106 cells. In contrast, the rate of angiotensinogen secretion decreased regularly from 45 arbitrary units/106 cells/h at 2 h, to half this value at 6 h, although cell content remained constant at 100 arbitrary units/106 cells. Inhibition of protein synthesis by cycloheximide depleted the cells from leptin, but not from angiotensinogen for up to 6 h. Insulin increased leptin secretion (+75%) and cell content (+70 %), without affecting angiotensinogen. Secretion of both proteins was inhibited by Golgi‐disturbing agents, brefeldin A and monensin. The presence of brefeldin A led to a specific rise in leptin cell content, an effect inhibited by cycloheximide and enhanced by insulin (+80%). These data show that leptin and angiotensinogen are both secreted through Golgi‐dependent pathways and that their respective intracellular pool exhibit distinct turn‐over rate and insulin sensitivity. These characteristics might account for the differential response of these adipose proteins to variations in the systemic environment. J. Cell. Biochem. 82: 666–673, 2001.

Embryonic expression of the leptin receptor gene in mesoderm-derived tissues

Leptin acts on the hypothalamus to reduce food intake and on a number of non-neuronal tissues via specific receptors (Lepr). The use of in situ hybridisation to map the Lepr gene in pre-natal mice revealed transcripts in the yolk sac in various structures of the central nervous system and in mesoderm-derived tissues, such as cartilage/bone primordia and musculoaponeurotic laminae. At later stages, significant amounts of Lepr were expressed in the region surrounding the developing eye of the embryo. Lepr was also found to be expressed in the choroid, sclera and connective tissues of the limbus in the adult eye. In conclusion, we have identified new targets for leptin action during embryogenesis and adulthood.