Filtern
Erscheinungsjahr
- 2020 (4) (entfernen)
Dokumenttyp
- Wissenschaftlicher Artikel (1)
- Dissertation (1)
- Postprint (1)
- Rezension (1)
Sprache
- Englisch (4)
Gehört zur Bibliographie
- ja (4)
Schlagworte
- FGF21 (4) (entfernen)
Institut
Aging has been viewed both as a random process due to accumulation of molecular and cellular damage over time and as a programmed process linked to cellular pathway important for growth and maturation. These views converge on mitochondria as both the major producer of damaging reactive oxidant species (ROS) and as signaling organelles. A finite proton leak across the inner mitochondrial membrane leading to a slight uncoupling of oxidative phosphorylation and respiration is an intrinsic property of all mitochondria and according to the "uncoupling to survive" hypothesis it has evolved to protect against ROS production to minimize oxidative damage. This hypothesis is supported by evidence linking an increased endogenous, uncoupling protein (UCP1) mediated, as well as experimentally induced mitochondrial uncoupling to an increased lifespan in rodents. This is possibly due to the synergistic activation of molecular pathways linked to life extending effects of caloric restriction as well as a mitohormetic response. Mitohormesis is an adaptive stress response through mitonuclear signaling which increases stress resistance resulting in health promoting effects. Part of this response is the induction of fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), two stress-induced mitokines which elicit beneficial systemic metabolic effects via endocrine action.
Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.
Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass.
Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.
Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.
Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.
Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass.
Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.
Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.
The hepatokine FGF21 and the adipokine chemerin have been implicated as metabolic regulators and mediators of inter-tissue crosstalk. While FGF21 is associated with beneficial metabolic effects and is currently being tested as an emerging therapeutic for obesity and diabetes, chemerin is linked to inflammation-mediated insulin resistance. However, dietary regulation of both organokines and their role in tissue interaction needs further investigation.
The LEMBAS nutritional intervention study investigated the effects of two diets differing in their protein content in obese human subjects with non-alcoholic fatty liver disease (NAFLD). The study participants consumed hypocaloric diets containing either low (LP: 10 EN%, n = 10) or high (HP: 30 EN%, n = 9) dietary protein 3 weeks prior to bariatric surgery. Before and after the intervention the participants were anthropometrically assessed, blood samples were drawn, and hepatic fat content was determined by MRS. During bariatric surgery, paired subcutaneous and visceral adipose tissue biopsies as well as liver biopsies were collected. The aim of this thesis was to investigate circulating levels and tissue-specific regulation of (1) FGF21 and (2) chemerin in the LEMBAS cohort. The results were compared to data obtained in 92 metabolically healthy subjects with normal glucose tolerance and normal liver fat content.
(1) Serum FGF21 concentrations were elevated in the obese subjects, and strongly associated with intrahepatic lipids (IHL). In accordance, FGF21 serum concentrations increased with severity of NAFLD as determined histologically in the liver biopsies. Though both diets were successful in reducing IHL, the effect was more pronounced in the HP group. FGF21 serum concentrations and mRNA expression were bi-directionally regulated by dietary protein, independent from metabolic improvements. In accordance, in the healthy study subjects, serum FGF21 concentrations dropped by more than 60% in response to the HP diet. A short-term HP intervention confirmed the acute downregulation of FGF21 within 24 hours. Lastly, experiments in HepG2 cell cultures and primary murine hepatocytes identified nitrogen metabolites (NH4Cl and glutamine) to dose-dependently suppress FGF21 expression.
(2) Circulating chemerin concentrations were considerably elevated in the obese versus lean study participants and differently associated with markers of obesity and NAFLD in the two cohorts. The adipokine decreased in response to the hypocaloric interventions while an unhealthy high-fat diet induced a rise in chemerin serum levels. In the lean subjects, mRNA expression of RARRES2, encoding chemerin, was strongly and positively correlated with expression of several cytokines, including MCP1, TNFα, and IL6, as well as markers of macrophage infiltration in the subcutaneous fat depot. However, RARRES2 was not associated with any cytokine assessed in the obese subjects and the data indicated an involvement of chemerin not only in the onset but also resolution of inflammation. Analyses of the tissue biopsies and experiments in human primary adipocytes point towards a role of chemerin in adipogenesis while discrepancies between the in vivo and in vitro data were detected.
Taken together, the results of this thesis demonstrate that circulating FGF21 and chemerin levels are considerably elevated in obesity and responsive to dietary interventions. FGF21 was acutely and bi-directionally regulated by dietary protein in a hepatocyte-autonomous manner. Given that both, a lack in essential amino acids and excessive nitrogen intake, exert metabolic stress, FGF21 may serve as an endocrine signal for dietary protein balance. Lastly, the data revealed that chemerin is derailed in obesity and associated with obesity-related inflammation. However, future studies on chemerin should consider functional and regulatory differences between secreted and tissue-specific isoforms.