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  • The role of circulating physiologic concentrations of FGF in

    2024-07-09

    The role of circulating physiologic concentrations of FGF21 in glucose metabolism, however, remains unclear. Circulating FGF21 levels in obese and diabetic rodents, and in patients with type 2 diabetes are significantly higher than those in controls without diabetes [4], [5], [6]. On the other hand, in a large prospective study of Chinese subjects, the circulating FGF21 levels increased as prediabetic patients progressed to diabetes; i.e., as dysglycemia increased and normal glucose tolerance deteriorated [7]. FGF21 may therefore be a potential biomarker that predicts the risk of type 2 diabetes. In addition, FGF21 is induced by a variety of environmental and metabolic stimuli, including changes in nutritional status, and it mediates the adaptive responses to stress [8]. FGF21 acts centrally to exert its effects on mineralocorticoid receptor expenditure and body weight via the sympathetic nervous system in obese mice [9]. The role of the adrenergic receptors in regulating plasma FGF21 levels, however, has not been evaluated.
    Materials and methods
    Results
    Discussion The results of the present study demonstrated that pharmacologic blockade of α-adrenergic receptor, especially α1-adrenergic receptor, rapidly increased plasma FGF21 levels independently of feeding in mice. FGF21 is induced directly by PPARα in liver in response to fasting, PPARα agonists, and a high-fat, low-carbohydrate ketogenic diet [13], [14]. In addition, FGF21 is a downstream target of PPARγ and is required for the anti-diabetic effects of PPARγ agonists [15]. We have previously reported that intraperitoneal administration of liraglutide, a glucagon-like-peptide 1 (GLP-1) receptor agonist, increases hepatic FGF21 production associated with increased expression of hepatic PPARγ but not PPARα in fed mice [11]. Our results, however, demonstrated that the α1-adrenergic receptor blockade rapidly increased the expression of hepatic FGF21 independently of PPARα and PPARγ. Thus, the increased hepatic FGF21 production induced by the α1-adrenergic receptor blockade might be due to the different mechanisms than fasting, PPARα agonists, a high-fat, low-carbohydrate ketogenic diet, PPARγ agonists or the GLP-1 receptor agonist. Transgenic mice that overexpress FGF21 exhibit reduced plasma glucose, insulin, triglyceride, cholesterol levels, and increased insulin sensitivity and resistance to diet-induced and age-induced weight gain and fat accumulation [3]. The phenotype of mice that stably overexpress human FGF21 at plasma levels of approximately 100ng/ml (i.e., 500 times higher than basal [3], [4], [11], [12]) is consistent with FGF21 pharmacology. FGF21 physiologic concentrations in plasma are no greater than a few hundred picograms per milliliter [11], [12], [13], [14], which is consistent with our results. Unexpectedly, despite the increased plasma FGF21 levels, administration of the α1-adrenergic receptor blockade impaired glucose tolerance in normal mice. Our present results support previous findings that blood glucose levels are higher after oral glucose and prazosin than after glucose only in non-diabetic subjects [16]. From these findings, we raise the hypothesis that the increases in physiologic circulating FGF21 concentrations in the fasted state may be related to impaired glucose tolerance.
    Conflict of interest
    Acknowledgment
    Introduction In humans, the consumption of a high-fat, low-carbohydrate KD leads to weight-loss and improves glucose tolerance, with no adverse effects on lipid profile [4]. In mice, we have previously shown that KD feeding leads to a distinct metabolic state characterized by weight loss, increased energy expenditure, activation of BAT, increased systemic insulin sensitivity, and a distinct pattern of hepatic gene expression [1]. Subsequently, we evaluated long-term effects of KD feeding and found long-term resistance to weight-gain on this diet by WT mice with no adverse effects on morbidity and mortality [5].