FGF21 regulates insulin sensitivity following long-term chronic stress

Dille, Matthias; Müller-Lühlhoff, Sabrina; Kabra, Dhiraj G.; Zhou, Zhou; Binsch, Christian; Hartwig, Sonja; Lehr, Stefan; Chadt, Alexandra; Peters, Eva M.J.; Kruse, Johannes; Roden, Michael; Al-Hasani, Hadi; Castañeda, Tamara R.

doi:10.1016/j.molmet.2018.06.012

Cited by 21 publications

(25 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation is in line with mouse studies suggesting that growth hormone induced FGF21 serum levels depend on increased adipose tissue lipolysis [68]. For cortisol, no associations with FGF21 levels could be found in patients with chronically elevated cortisol levels (Cushing syndrome) [69], or in stressed (healthy) humans [70]. Human data directly confirming or rejecting the regulatory effects of cortisol on FGF21 levels are yet missing, In mice, a role for GLP1-FGF21 axis involving adipose tissue immune cells (invariant natural killer T (iNKT)) in regulating weight and glucose homeostasis by promoting WAT browning was shown [71].…”

Section: Hormonal Regulation Of Circulating Fgf21 Levelssupporting

confidence: 88%

Circulating FGF21 Levels in Human Health and Metabolic Disease

Keuper

Häring

Staiger

2019

Exp Clin Endocrinol Diabetes

View full text Add to dashboard Cite

Human fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor beta-Klotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21’s role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.

show abstract

Section: Hormonal Regulation Of Circulating Fgf21 Levelssupporting

confidence: 88%

Circulating FGF21 Levels in Human Health and Metabolic Disease

Keuper

Häring

Staiger

2019

Exp Clin Endocrinol Diabetes

View full text Add to dashboard Cite

show abstract

“…We observed that chronic restraint stress (CRS) can lead to insulin resistance and hyperglycemia in no more than 50% rat (Liang et al, 2013). Mice exposed to chronic variable stress also showed decreased insulin sensitivity (Jelenik et al, 2018). So, is stress-induced hyperglycemia a direct effect of glucocorticoids?…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemia Induced by Chronic Restraint Stress in Mice Is Associated With Nucleus Tractus Solitarius Injury and Not Just the Direct Effect of Glucocorticoids

Zheng

Yang

et al. 2018

Front. Neurosci.

View full text Add to dashboard Cite

Chronic restraint stress (CRS) can affect hypothalamic-pituitary-adrenal (HPA) axis activity and increase glucocorticoid levels. Glucocorticoids are stress hormones that regulate multiple aspects of energy homeostasis. Stress also impairs glucose tolerance. The aim of this study was to investigate the cause of insulin-resistant hyperglycemia during CRS. We produced the CRS models (a 7-day restraint followed by a 3-day free moving procedure, total of 4 cycles for 40 days) in mice, detected the parameters related to glucose metabolism, and compared them to those of the dexamethasone (DEX) injection (0.2 mg/kg i.p., also a 4 cycle procedure as the CRS). The results showed that the CRS induced a moderate (not higher than 11 mmol/L) and irreversible insulin-resistant hyperglycemia in about 1/3 of the individuals, and all the restrained mice had adrenal hypertrophy. CRS induced the apoptosis of neurons in the anterior part of commissural subnucleus of nucleus tractus solitarius (acNTS) in the hyperglycemic mice, and acNTS mechanical damage also led to insulin-resistant hyperglycemia. In contrast, in the DEX-treated mice, adrenal gland atrophy was evident. The glucose and insulin tolerance varied with the delay of determination. DEX exposure in vivo does not induce the apoptosis of neurons in NTS. This study indicates that restraint stress and DEX induce metabolic disorders through different mechanisms. During CRS, injury (apoptosis) of glucose-sensitive acNTS neurons cause dysregulation of blood glucose. This study also suggests the mouse restraint stress model has value as a potential application in the study of stress-induced hyperglycemia.

show abstract

“…FGF21 levels in cerebrospinal fluid were found to be negatively related to the scores of Beck Depression Inventory in male participants (23). Additionally, circulating levels of FGF21 were found to be positively correlated with the abilities to cope with stress after chronic exposure (24). Moreover, the magnitude of increase in serum FGF21 levels was found to be associated with the treatment effects of antidepressant drugs (16), though no significant correlation had been observed in female participants (23).…”

Section: Discussionmentioning

confidence: 93%

FGF21 mediates the anti-depressant effects of exercise by coordinating the crosstalk between central and peripheral organs

et al. 2020

View full text Add to dashboard Cite

Exercise is an effec ve an-depressant treatment; however, its underlying mechanism remains largely unknown. Fibroblast growth factor 21 (FGF21) is a metabolic hormone cri cally involved in energy metabolism. Here, we showed that FGF21 knockout significantly diminished exercise-elicited an-depressant effects, while replenishment with recombinant FGF21 effec vely restored the effects of exercise on allevia on of depression by suppressing neuroinflamma on, enhancing adult neurogenesis and synap c plas city in the hippocampus. However, the FGF21 co-receptor β-klotho was not expressed in hippocampal neurons. The an-depressant property of FGF21 was a ributed to its ability to s mulate adipocyte secre on of adiponec n, which func oned as a downstream effector of FGF21 to confer the an-depressant effects. Collec vely, these data iden fy FGF21 as an important player in media ng the an-depressant effects of exercise, possibly by coordina ng mul-organ crosstalk among liver, adipose ssue and brain, and also raise the possibility that FGF21 and its agonists may represent a promising therapeu c approach for depression.

show abstract

FGF21 regulates insulin sensitivity following long-term chronic stress

Cited by 21 publications

References 51 publications

Circulating FGF21 Levels in Human Health and Metabolic Disease

Circulating FGF21 Levels in Human Health and Metabolic Disease

Hyperglycemia Induced by Chronic Restraint Stress in Mice Is Associated With Nucleus Tractus Solitarius Injury and Not Just the Direct Effect of Glucocorticoids

FGF21 mediates the anti-depressant effects of exercise by coordinating the crosstalk between central and peripheral organs

Contact Info

Product

Resources

About