Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans

Abstract

Background & aimsFibroblast growth factor 21 (FGF-21) is a liver-derived metabolic regulator induced by energy deprivation. However, its regulation in humans is incompletely understood. We addressed the origin and regulation of FGF-21 secretion in humans.MethodsBy determination of arterial-to-venous differences over the liver and the leg during exercise, we evaluated the organ-specific secretion of FGF-21 in humans. By four different infusion models manipulating circulating glucagon and insulin, we addressed the interaction of these hormones on FGF-21 secretion in humans.ResultsWe demonstrate that the splanchnic circulation secretes FGF-21 at rest and that it is rapidly enhanced during exercise. In contrast, the leg does not contribute to the systemic levels of FGF-21. To unravel the mechanisms underlying the regulation of exercise-induced hepatic release of FGF-21, we manipulated circulating glucagon and insulin. These studies demonstrated that in humans glucagon stimulates splanchnic FGF-21 secretion whereas insulin has an inhibitory effect.ConclusionsCollectively, our data reveal that 1) in humans, the splanchnic bed contributes to the systemic FGF-21 levels during rest and exercise; 2) under normo-physiological conditions FGF-21 is not released from the leg; 3) a dynamic interaction of glucagon-to-insulin ratio regulates FGF-21 secretion in humans.

Modulation of energy balance by fibroblast growth factor 21

“…Our group was the first to report increased FGF21 levels after intense physical activity in sedentary young women, which was significantly and independently correlated with noradrenaline levels and FFAs, suggesting that increase sympathetic activity and lipolysis was the mechanism that induce FGF21 augmentation [20]. The effect of exercise in FGF21 levels were consistent with other studies [21,22], as well as the key role of adrenergic activity to induce FGF21 expression [23]. Conditions with high FFAs mobilization or under increased chronic inflammation such as lactation, patients under growth hormone treatment, insulin resistance, heart ischemic disease, hypothyroidism, and kidney failure associated with preeclampsia have higher circulating FGF21 levels [15,[25][26][27][28][29].…”

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

“…This study has been described elsewhere (18). In brief, 10 healthy males (age, 22.9 Ϯ 0.8; body mass index [BMI], 22.6 Ϯ 0.5; maximum oxygen consumption, 51.0 Ϯ 1.2 ml/kg/min) performed 2 hours of bicycle exercise at 60% maximum oxygen consumption in the semisupine position with catheters placed in an antecubital vein, a hepatic vein, and brachial artery, allowing for arterial-venous measurements over the liver.…”

“…This study has been described elsewhere (18). Ten healthy males went through four experimental protocols (test days 1-4).…”

“…To investigate whether glucagon and insulin acutely regulate circulating follistatin, the glucagon-to-insulin ratio was manipulated in physiologically relevant doses and durations in four different trials (see reference (18) for details); 1) high glucagon/high insulin, 2) high glucagon/ low insulin, 3) low glucagon/low insulin, and 4) control trial with saline infusion.…”

“…Interestingly, this phenomenon is also observed for FGF-21 (18), demonstrating a similar regulatory mechanism for these two hepatokines in vivo. In response to exercise, FGF-21 peaks 30 minutes after the end of the exercise and returns to baseline levels 2 hours after the exercise bout (18). Exercise-induced follistatin increases 1 hour after exercise and remains elevated up to 6 hours after exercise (11).…”