Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio

Abstract

In conclusion, in humans, the liver secretes follistatin at rest and during exercise, and the glucagon-to-insulin ratio is a key determinant of circulating follistatin levels. Circulating follistatin may be a marker of the glucagon-to-insulin tone on the liver.

Circulating follistatin displays a day–night rhythm and is associated with muscle mass and circulating leptin levels in healthy, young humans

“…Exercise has been reported to acutely increase plasma follistatin [7]; however, this increase is more likely derived from liver rather than from muscle production [6, 7, 27]. Circulating follistatin levels were not affected by the physical activity habits in this study suggesting that the acute effect is lost in a long-term basis.…”

“…This effect could mean that follistatin acts as a mediator by which the consumed glucose and proteins are directed to the muscles to support muscle tissue growth. This might not be the case for consumed lipids, as Hansen et al reported that intralipid infusion resulted in decreased follistatin levels [6]. It has also been previously reported that chronic energy deprivation increases follistatin levels in both healthy males [8] and females [28].…”

“…Thus, circulating follistatin was considered to originate mainly from such paracrine actions. However, follistatin has been proposed to be an adipokine [5] while recent data suggest an endocrine production from the liver [6] in response to stimuli such as acute exercise [7] or feeding status [8] and the physiological role of follistatin and follistatin-like molecules has expanded to the regulation of fat and lean mass and muscle growth, through activin and myostatin inhibition [2, 9]. Furthermore, follistatin has been implicated in the pathogenesis of muscle atrophy [3] and of metabolic diseases, as it has been reported to be elevated in patients with type 2 diabetes [10], polycystic ovary syndrome (PCOs) [11] and nonalcoholic fatty liver disease (NAFLD) [12].…”

Activin A and follistatin in patients with nonalcoholic fatty liver disease

“…Notably, our findings indicate that follistatin loses its independent association with NASH, when central adiposity or IR are taken into account, which may imply either that follistatin is a marker reflecting central obesity and/or IR status or that follistatin is induced by central obesity and IR, but the potential counterbalancing follistatin action is not sufficient to limit disease progression. This is important in the light of the recent observation that the liver is a major contributor to circulating follistatin, where insulin inhibits and glucagon increases follistatin secretion in the hepatocyte [13]. However, mechanistic studies and long-term prospective studies are required to clarify the validity of our hypotheses.…”

“…It has been recently proposed that the liver is a major contributor to the circulating levels of follistatin in humans [13]. Deregulated expression of follistatin and activins has been implicated in hepatic diseases, including inflammation, fibrosis, liver failure and hepatocellular carcinoma [14].…”