FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology

The FGF family comprises twenty-two structurally related proteins with functions in development and metabolism. The Fgf21 gene was generated early in vertebrate evolution. FGF21 acts as an endocrine regulator in lipid metabolism. Hepatic Fgf21 expression is markedly induced in mice by fasting or a ketogenic diet. Experiments with Fgf21 transgenic mice and cultured cells indicate that FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes via cell surface FGF receptors. However, experiments with Fgf21 knockout mice indicate that FGF21 inhibits lipolysis in adipocytes during fasting and attenuates torpor induced by a ketogenic diet but maybe not a physiological regulator for these hepatic functions. These findings suggest the pharmacological effects to be distinct from the physiological roles. Serum FGF21 levels are increased in patients with metabolic diseases having insulin resistance, indicating that FGF21 is a metabolic regulator and a biomarker for these diseases

Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood

The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) α–dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction of hepatic FGF21 expression after PPARα activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity

Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle–specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance

Neucrin is a novel neural-specific secreted antagonist to canonical Wnt signaling

A gene encoding a novel secreted protein in mice and humans was identified, and named Neucrin. Mouse Neucrin consists of 343 amino acids with a cysteine-rich domain in its carboxyl terminal region. The positions of 10 cysteine residues in the cysteine-rich domain are similar to those of Dickkopfs (Dkks), secreted Wnt antagonists. However, whereas Dkks have two cysteine-rich domains, Neucrin has only one. Neucrin as well as Dkks bound to LDL receptor-related protein 6 and inhibited the stabilization of cytosolic β-catenin, indicating that Neucrin is an antagonist of canonical Wnt signaling. Mouse Neucrin expression was not detected in any major tissues in the adult, but was detected in developing neural tissues, including the brain and spinal cord. The expression pattern of Neucrin is distinct from that of any Dkk. Neucrin is a unique secreted Wnt antagonist that is predominantly expressed in developing neural tissues

Roles of FGF signals in heart development, health, and disease

The heart provides the body with oxygen and nutrients and assists in the removal of metabolic waste through the blood vessels of the circulatory system. It is the first organ to form during embryonic morphogenesis. FGFs with diverse functions in development, health, and disease are signaling proteins, mostly as paracrine growth factors or endocrine hormones. The human/mouse FGF family comprises 22 members. Findings obtained from mouse models and human diseases with FGF signaling disorders have indicated that several FGFs are involved in heart development, health, and disease. Paracrine FGFs including FGF8, FGF9, FGF10, and FGF16 act as paracrine signals in embryonic heart development. In addition, paracrine FGFs including FGF2, FGF9, FGF10, and FGF16 play roles as paracrine signals in postnatal heart pathophysiology. Although FGF15/19, FGF21, and FGF23 are typical endocrine FGFs, they mainly function as paracrine signals in heart development or pathophysiology. In heart diseases, serum FGF15/19 levels or FGF21 and FGF23 levels decrease or increase, respectively, indicating their possible roles in heart pathophysiology. FGF2 and FGF10 also stimulate the cardiac differentiation of cultured stem cells and cardiac reprogramming of cultured fibroblasts. These findings provide new insights into the roles of FGF signaling in the heart and potential therapeutic strategies for cardiac disorders

Functions of MAPR (Membrane-Associated Progesterone Receptor) Family Members As Heme/Steroid-Binding Proteins

Progesterone receptor membrane component 1 (PGRMC1), PGRMC2, neudesin, and neuferricin all contain a cytochrome b5-like heme/steroid-binding domain and belong to the membrane-associated progesterone receptor (MAPR) family. Their amino acid sequences are well conserved among vertebrates, from humans to zebrafish. MAPR family genes are abundantly expressed in the central nervous system and exhibit neurotrophic effects in neural cells. During lipid metabolism, PGRMC1 regulates cholesterol synthesis, and neudesin plays a role in adipogenesis. Their bioactivities are dependent on the binding of heme to their cytochrome b5-like heme/steroid-binding domains. Conversely, it has been reported that the binding of steroids to MAPR family proteins induces biological responses that are unrelated to the nuclear steroid receptors. The interaction between PGRMC1 and progesterone promotes cell survival and damage resistance by progesterone. Moreover, MAPR family proteins exhibit a unique expression pattern in breast cancer, indicating the possibility of using MAPR family members as drug target in breast cancer. In this review, we summarize the identification, structure, and bioactivity of members of the MAPR family, and present an essential overview of the current understanding of their physiological roles

Fgf16 is required for specification of GABAergic neurons and oligodendrocytes in the zebrafish forebrain.

Fibroblast growth factor (Fgf) signaling plays crucial roles in various developmental processes including those in the brain. We examined the role of Fgf16 in the formation of the zebrafish brain. The knockdown of fgf16 decreased cell proliferation in the forebrain and midbrain. fgf16 was also essential for development of the ventral telencephalon and diencephalon, whereas fgf16 was not required for dorsoventral patterning in the midbrain. fgf16 was additionally required for the specification and differentiation of γ-aminobutyric acid (GABA)ergic interneurons and oligodendrocytes, but not for those of glutamatergic neurons in the forebrain. Cross talk between Fgf and Hedgehog (Hh) signaling was critical for the specification of GABAergic interneurons and oligodendrocytes. The expression of fgf16 in the forebrain was down-regulated by the inhibition of Hh and Fgf19 signaling, but not by that of Fgf3/Fgf8 signaling. The fgf16 morphant phenotype was similar to that of the fgf19 morphant and embryos blocked Hh signaling. The results of the present study indicate that Fgf16 signaling, which is regulated by the downstream pathways of Hh-Fgf19 in the forebrain, is involved in forebrain development

FGF21欠損マウスにおいて社会的ストレスが睡眠へ及ぼす影響

Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress