Endocrine Abstracts (2008) 16 S2.3

TGF-[beta] family ligands in glucose and fat homeostasis in adults

Alan Schneyer1, Susan Bonner-Weir2, Abir Mukherjee4, Yisrael Sidis3 & Melissa Thomas3

1Pioneer Valley Life Science Institute, Sprinfield, Massachusetts, USA; 2Joslin Diabetes Center, Boston, Massachusetts, USA; 3Massachusetts General Hospital, Boston, Massachusetts, USA; 4Royal Veterinary College, London, UK.

The bioavailability of activin, GDF11, and myostatin, members of the TGFβ superfamily, is regulated by the soluble antagonists follistatin (FST) and follistatin like-3 (FSTL3). Activin influences tissue fate determination and organogenesis in embryos as well as organ homeostasis in adults while myostatin decreases muscle mass in adults and GDF11 regulates pancreatic β-cell differentiation. In addition, the FST gene produces three protein forms (FST288, FST303, and FST315) with different bioactivities and distributions within the body. Despite a great deal of biochemical and molecular knowledge, the precise physiological roles of FSTL3 and FST in regulating TGFβ ligands in the adult remain to be determined.

We have made several mouse genetic models designed to investigate the biological roles of FST and FSTL3 in adults. In contrast to FST KO mice, which die at birth, FSTL3 KO mice are born and survive like WT littermates. These mice, however, have larger testes, suggesting that FSTL3 regulates activin-mediated Sertoli cell proliferation. FSTL3 KO mice also have a number of metabolic phenotypes including enlarged pancreatic islets with β-cell hyperplasia, enhanced glucose tolerance and insulin sensitivity, hepatic steatosis, and reduced visceral fat mass. These enlarged islets are not evident in 2–3 months old mice indicating that activin and/or GDF11 have important roles in regulating islet size and β-cell number in adults. We have also made mice in which only the FST288 isoform is expressed (no circulating FST315 isoform). These FST288-only mice are viable and initially appear healthy, indicating that the FST288 isoform is sufficient to circumvent the global FST KO lethality. However, FST288-only mice exhibit reduced fertility. Moreover, they also develop enhanced glucose tolerance and insulin sensitivity, as well as hepatic steatosis, similar to the FSTL3 KO mice. Taken together, these mouse models indicate that FSTL3 and FST315, presumably through regulation of activin, GDF11 and myostatin bioactivity, have previously unappreciated activities in adults that may influence islet size and composition, glucose homeostasis, fat metabolism, and liver disease.

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