Follistatin and Follistatin Like‐3 Differentially Regulate Adiposity and Glucose Homeostasis

Abstract

TGFβ superfamily ligands, including activin and myostatin, modulate body composition, islet function, and glucose homeostasis. Their bioactivity is controlled by the antagonists follistatin (FST) and follistatin like-3 (FSTL3). The hypothesis tested was that FST and FSTL3 have distinct roles in regulating body composition, glucose homeostasis and islet function through regulation of activin and myostatin bioactivity. Three genetic mutant mouse lines were created. FSTL3 knockout (FSTL3 KO), a mouse line producing only the FST288 isoform (FST288-only) and a double mutant (2xM) in which the lines were crossed. FST288-only males were lighter that WT littermates while FSTL3 KO and 2xM males had reduced perigonadal fat pad weights. However, only 2xM mice had increased whole body fat mass and decreased lean mass by qNMR. Fasting glucose levels in FSTL3 WT and KO mice were lower than FST mice in younger animals but were higher in older mice. Serum insulin and pancreatic insulin content in 2xM mice was significantly elevated over other genotypes. Nevertheless, 2xM mice were relatively insulin resistant and glucose intolerant compared to FST288-only and WT mice. Fractional islet area and proportion of β-cells/islet were increased in FSTL3 KO and 2xM, but not FST288-only mice. Despite their larger size, islets from FSTL3 KO and 2xM mice were not functionally enhanced compared to WT mice. These results demonstrate that body composition and glucose homeostasis are differentially regulated by FST and FSTL3 and that their combined loss is associated with increased fat mass and insulin resistance despite elevated insulin production.

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

“…Encoded by FST, the protein follistatin has been shown to promote adipocyte differentiation and reduce fat mass and insulin resistance. 70,71 The same GWAS variant showed no eQTL for the nearest gene, ARL15 (p ¼ 0. 43)…”

Follistatin-Like 3 Across Gestation in Preeclampsia and Uncomplicated Pregnancies Among Lean and Obese Women

“…Circulating lipids, measures of insulin sensitivity versus resistance, and adipocyte function might be better indicators of fat metabolism than the body composition measures of adiposity. 9,10,[13][14][15]40 Other pathways affected by metabolic disturbances associated with obesity, such as adipokines, inflammation, and oxidative stress, also need to be investigated in relation to FSTL-3 in pregnancy and preeclampsia.…”

“…12 Loss of FSTL3 in animals has been reported to increase insulin sensitivity and is associated with increased subcutaneous body fat, reduced visceral fat, and binds myostatin, a TGF-b protein, which normally reduces muscle mass. [13][14][15] FSTL3 knockout mice are reported to develop hypertension by 9 months of age. 15 Follistatin-like 3 has been shown to be most highly expressed by the placenta, followed by testes, heart, and pancreas in ranked comparison with 18 other human tissues.…”

“…This was an exploratory aim since FSTL3 knockout mice exhibit lower visceral fat [13][14][15] ; however, higher visceral fat in women's first trimester is associated with an increased risk of developing preeclampsia. 23 Moreover, our prior study of obesity and proinflammatory cytokine tumor necrosis factor-alpha in preeclampsia led us to suggest that adipose distribution, rather than body mass index (BMI), might be a better indicator of inflammation and glucose metabolism in pregnancy.…”

FSTL3 (follistatin-like 3 (secreted glycoprotein))

“…FSTL3 knock-out mice had increased pancreatic island number and size, enhanced insulin sensitivity and hepatic steatosis suggesting a role of FSTL3 in glucose and fat homeostasis (Mukherjee et al, 2007). Combined knockout of FSTL3 and follistatin, however, led to increased fat mass and insulin resistance despite elevated insulin production (Brown et al, 2011).…”