Publications by authors named "Susanne Klaus"

88 Publications

Postprandial dynamics and response of fibroblast growth factor 21 in older adults.

Clin Nutr 2021 Jun 27;40(6):3765-3771. Epub 2021 Apr 27.

German Institute of Human Nutrition, Potsdam-Rehbrücke, Department of Nutrition and Gerontology, Nuthetal, Germany; University of Potsdam, Institute of Nutritional Science, Potsdam, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Geriatrics, Berlin, Germany. Electronic address:

Background & Aims: Fibroblast growth factor 21 (FGF21) plays a pivotal role in glucose and lipid metabolism and has been proposed as a longevity hormone. However, elevated plasma FGF21 concentrations are paradoxically associated with mortality in higher age and little is known about the postprandial regulation of FGF21 in older adults. In this parallel group study, we investigated postprandial FGF21 dynamics and response in older (65-85 years) compared to younger (18-35 years) adults following test meals with varying macronutrient composition.

Methods: Participants (n = 60 older; n = 60 younger) were randomized to one of four test meals: dextrose, high carbohydrate (HC), high fat (HF) or high protein (HP). Blood was drawn before and 15, 30, 60, 120, 240 min after meal ingestion. Postprandial dynamics were evaluated using repeated measures ANCOVA. FGF21 response was assessed by incremental area under the curve.

Results: Fasting FGF21 concentrations were significantly higher in older adults. FGF21 dynamics were affected by test meal (p < 0.001) and age (p = 0.013), when adjusted for BMI and fasting FGF21. Postprandial FGF21 concentrations steadily declined over 240 min in both age groups after HF and HP, but not after dextrose or HC ingestion. At 240 min, FGF21 concentrations were significantly higher in older than in younger adults following dextrose (133 pg/mL, 95%CI: 103, 172 versus 91.2 pg/mL, 95%CI: 70.4, 118; p = 0.044), HC (109 pg/mL, 95%CI: 85.1, 141 versus 70.3 pg/mL, 95%CI: 55.2, 89.6; p = 0.014) and HP ingestion (45.4 pg/mL, 95%CI: 34.4, 59.9 versus 27.9 pg/mL 95%CI: 20.9, 37.1; p = 0.018). FGF21 dynamics and response to HF were similar for both age groups.

Conclusions: The age-specific differences in postprandial FGF21 dynamics and response in healthy adults, potentially explain higher FGF21 concentrations in older age. Furthermore, there appears to be a significant impact of acute and recent protein intake on FGF21 secretion.
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http://dx.doi.org/10.1016/j.clnu.2021.04.037DOI Listing
June 2021

Effect of Microbial Status on Hepatic Odd-Chain Fatty Acids Is Diet-Dependent.

Nutrients 2021 May 4;13(5). Epub 2021 May 4.

Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.

Odd-chain fatty acids (OCFA) are inversely associated with type-2-diabetes in epidemiological studies. They are considered as a biomarker for dairy intake because fermentation in ruminants yields high amounts of propionate, which is used as the primer for lipogenesis. Recently, we demonstrated endogenous OCFA synthesis from propionate in humans and mice, but how this is affected by microbial colonization is still unexplored. Here, we investigated the effect of increasing microbiota complexity on hepatic lipid metabolism and OCFA levels in different dietary settings. Germ-free (GF), gnotobiotic (SIH, simplified human microbiota) or conventional (CONV) C3H/HeOuJ-mice were fed a CHOW or high-fat diet with inulin (HFI) to induce microbial fermentation. We found that hepatic lipogenesis was increased with increasing microbiota complexity, independently of diet. In contrast, OCFA formation was affected by diet as well as microbiota. On CHOW, hepatic OCFA and intestinal gluconeogenesis decreased with increasing microbiota complexity (GF > SIH > CONV), while cecal propionate showed a negative correlation with hepatic OCFA. On HFI, OCFA levels were highest in SIH and positively correlated with cecal propionate. The propionate content in the CHOW diet was 10 times higher than that of HFI. We conclude that bacterial propionate production affects hepatic OCFA formation, unless this effect is masked by dietary propionate intake.
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http://dx.doi.org/10.3390/nu13051546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147859PMC
May 2021

Pseudo-Starvation Driven Energy Expenditure Negatively Affects Ovarian Follicle Development.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

German Institute of Human Nutrition in Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.

In the present investigation, we examined whether a change in whole body energy fluxes could affect ovarian follicular development, employing mice ectopically expressing uncoupling protein 1 in skeletal muscle (UCP1-TG). Female UCP1-TG and wild-type (WT) mice were dissected at the age of 12 weeks. Energy intake and expenditure, activity, body weight and length, and body composition were measured. Plasma insulin, glucose, leptin, plasma fibroblast growth factor 21 (FGF21) and plasma insulin-like growth factor 1 (IGF1) levels were analyzed and ovarian follicle and corpus luteum numbers were counted. IGF1 signaling was analyzed by immunohistochemical staining for the activation of insulin receptor substrate 1/2 (IRS1/2) and AKT. UCP1-TG female mice had increased energy expenditure, reduced body size, maintained adiposity, and decreased IGF1 concentrations compared to their WT littermates, while preantral and antral follicle numbers were reduced by 40% and 60%, respectively. Corpora lutea were absent in 40% of the ovaries of UCP1-TG mice. Phospho-IRS1, phospho-AKT -Ser473 and -Thr308 immunostaining was present in the granulosa cells of antral follicles in WT ovaries, but faint to absent in the antral follicles of UCP1-TG mice. In conclusion, the reduction in circulating IGF1 levels due to the ectopic expression of UCP1 is associated with reduced immunostaining of the IRS1-PI3/AKT pathway, which may negatively affect ovarian follicle development and ovulation.
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http://dx.doi.org/10.3390/ijms22073557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036485PMC
March 2021

Regulation of diurnal energy balance by mitokines.

Cell Mol Life Sci 2021 Apr 19;78(7):3369-3384. Epub 2021 Jan 19.

Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.

The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.
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http://dx.doi.org/10.1007/s00018-020-03748-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814174PMC
April 2021

Age-related fatigue is associated with reduced mitochondrial function in peripheral blood mononuclear cells.

Exp Gerontol 2021 02 3;144:111177. Epub 2020 Dec 3.

German Institute of Human Nutrition, Potsdam - Rehbrücke, Department of Nutrition and Gerontology, Nuthetal, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Research Group on Geriatrics, Germany; University of Potsdam, Institute of Nutritional Science, Potsdam, Germany. Electronic address:

Background: Fatigue is a complex syndrome associated with exhaustion not relieved by sleep. It occurs frequently in older adults in the context of chronic disease and is associated with decreased physical capacity. Whether a mitochondrial dysfunction and therefore an impaired energy production might contribute to the development of fatigue during aging is yet unknown. The aim of this study was to evaluate mitochondrial respiration of peripheral blood mononuclear cells (PBMCs) in older patients with and without fatigue.

Method: Fatigue was determined according to the Brief Fatigue Inventory. Mitochondrial respiration of freshly isolated PBMCs was investigated by high-resolution respirometry using the Oroboros Oxygraph-O2k. Functional impairment and depressive symptoms were assessed using questionnaires.

Results: 23 geriatric patients (77.8 ± 4.9 years; 43.5% female) with fatigue and 22 without fatigue (75.4 ± 5.4 years; 45.5% female) were analyzed. Patients with fatigue exhibited more functional limitations and more depressive symptoms. High-resolution respirometry of intact PBMCs revealed a lower routine (4.82 ± 1.14 pmol/s versus 5.89 ± 1.90 pmol/s, p = 0.041) and maximum (6.55 ± 1.51 pmol/s versus 8.43 ± 3.67 pmol/s, p = 0.013) oxygen consumption rate, resulting in a reduced ATP-linked respiration (4.26 ± 1.00 pmol/s versus 5.09 ± 1.53 pmol/s, p = 0.035) of PBMCs from geriatric patients with fatigue compared to controls without.

Conclusions: This short report shows that in this group of older patients, fatigue is associated with lower PBMC mitochondrial respiration. Whether the impaired mitochondrial respiration is accompanied by a reduced mitochondrial activity in other organs (e.g. muscle) remains to be elucidated.
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http://dx.doi.org/10.1016/j.exger.2020.111177DOI Listing
February 2021

N-Acetylcysteine as Modulator of the Essential Trace Elements Copper and Zinc.

Antioxidants (Basel) 2020 Nov 12;9(11). Epub 2020 Nov 12.

Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, 07743 Jena, Germany.

N-acetylcysteine (NAC) is a frequently prescribed drug and known for its metal chelating capability. However, to date it is not well characterized whether NAC intake affects the homeostasis of essential trace elements. As a precursor of glutathione (GSH), NAC also has the potential to modulate the cellular redox homeostasis. Thus, we aimed to analyze effects of acute and chronic NAC treatment on the homeostasis of copper (Cu) and zinc (Zn) and on the activity of the redox-sensitive transcription factor Nrf2. Cells were exposed to 1 mM NAC and were co-treated with 50 μM Cu or Zn. We showed that NAC treatment reduced the cellular concentration of Zn and Cu. In addition, NAC inhibited the Zn-induced Nrf2 activation and limited the concomitant upregulation of cellular GSH concentrations. In contrast, mice chronically received NAC via drinking water (1 g NAC/100 mL). Cu and Zn concentrations were decreased in liver and spleen. In the duodenum, NQO1, TXNRD, and SOD activities were upregulated by NAC. All of them can be induced by Nrf2, thus indicating a putative Nrf2 activation. Overall, NAC modulates the homeostasis of Cu and Zn both in vitro and in vivo and accordingly affects the cellular redox balance.
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http://dx.doi.org/10.3390/antiox9111117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696987PMC
November 2020

Cell autonomous requirement of neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis.

J Cachexia Sarcopenia Muscle 2020 12 19;11(6):1758-1778. Epub 2020 Oct 19.

Musculoskeletal Development and Regeneration Group, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.

Background: Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in neurofibromin 1 (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients' mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy are mostly unknown.

Methods: To dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for NF1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analysed during prenatal and postnatal myogenesis and muscle growth.

Results: Nf1 and Nf1 animals showed only mild defects in prenatal myogenesis. Nf1 animals were perinatally lethal, while Nf1 animals survived only up to approximately 25 weeks. A comprehensive phenotypic characterization of Nf1 animals showed decreased postnatal growth, reduced muscle size, and fast fibre atrophy. Proteome and transcriptome analyses of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1 muscles, which was concomitant to a fibre type shift from type 2B to type 2A and type 1. Moreover, Nf1 muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1 animals, in line with a drastic reduction of white, but not brown adipose tissue.

Conclusions: Our results demonstrate a cell autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.
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http://dx.doi.org/10.1002/jcsm.12632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749575PMC
December 2020

High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels.

Liver Int 2020 12 21;40(12):2982-2997. Epub 2020 Jul 21.

Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany.

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent and nutrition intervention remains the most important therapeutic approach for NAFLD. Our aim was to investigate whether low- (LP) or high-protein (HP) diets are more effective in reducing liver fat and reversing NAFLD and which mechanisms are involved.

Methods: 19 participants with morbid obesity undergoing bariatric surgery were randomized into two hypocaloric (1500-1600 kcal/day) diet groups, a low protein (10E% protein) and a high protein (30E% protein), for three weeks prior to surgery. Intrahepatic lipid levels (IHL) and serum fibroblast growth factor 21 (FGF21) were measured before and after the dietary intervention. Autophagy flux, histology, mitochondrial activity and gene expression analyses were performed in liver samples collected during surgery.

Results: IHL levels decreased by 42.6% in the HP group, but were not significantly changed in the LP group despite similar weight loss. Hepatic autophagy flux and serum FGF21 increased by 66.7% and 42.2%, respectively, after 3 weeks in the LP group only. Expression levels of fat uptake and lipid biosynthesis genes were lower in the HP group compared with those in the LP group. RNA-seq analysis revealed lower activity of inflammatory pathways upon HP diet. Hepatic mitochondrial activity and expression of β-oxidation genes did not increase in the HP group.

Conclusions: HP diet more effectively reduces hepatic fat than LP diet despite of lower autophagy and FGF21. Our data suggest that liver fat reduction upon HP diets result primarily from suppression of fat uptake and lipid biosynthesis.
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http://dx.doi.org/10.1111/liv.14596DOI Listing
December 2020

The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism.

FASEB J 2020 07 7;34(7):9727-9739. Epub 2020 Jun 7.

Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.

Dairy intake, as a source of branched-chain amino acids (BCAA), has been linked to a lower incidence of type-2-diabetes and increased circulating odd-chain fatty acids (OCFA). To understand this connection, we aimed to investigate differences in BCAA metabolism of leucine and valine, a possible source of OCFA, and their role in hepatic metabolism. Male mice were fed a high-fat diet supplemented with leucine and valine for 1 week and phenotypically characterized with a focus on lipid metabolism. Mouse primary hepatocytes were treated with the BCAA or a Pparα activator WY-14643 to systematically examine direct hepatic effects and their mechanisms. Here, we show that only valine supplementation was able to increase hepatic and circulating OCFA levels via two pathways; a PPARα-dependent induction of α-oxidation and an increased supply of propionyl-CoA for de novo lipogenesis. Meanwhile, we were able to confirm leucine-mediated effects on the inhibition of food intake and transport of fatty acids, as well as induction of S6 ribosomal protein phosphorylation. Taken together, these data illustrate differential roles of the BCAA in lipid metabolism and provide preliminary evidence that exclusively valine contributes to the endogenous formation of OCFA which is important for a better understanding of these metabolites in metabolic health.
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http://dx.doi.org/10.1096/fj.202000195RDOI Listing
July 2020

Associations Between Serum GDF15 Concentrations, Muscle Mass, and Strength Show Sex-Specific Differences in Older Hospital Patients.

Rejuvenation Res 2021 Feb 23;24(1):14-19. Epub 2020 Jun 23.

Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.

Aging is accompanied by a progressive decline of muscle mass and strength and also higher levels of circulating cytokines such as growth differentiation factor 15 (GDF15). Studies evaluating the association of GDF15 with muscle mass and strength are rare. In this analysis, we investigated GDF15 concentrations and their relationship with muscle mass and strength in older men compared with women. GDF15 serum concentrations were measured in 103 (60 years and older) hospital patients and an age-matched control group with an immunosorbent assay. Skeletal muscle mass was determined with the bioelectrical impedance analysis. Grip strength and knee extension strength were assessed and normalized for height. Associations between GDF15 concentrations and muscle mass and strength were evaluated with general linear models. Male patients showed higher levels of GDF15 compared with female patients ( = 0.021). Elevated GDF15 concentrations were associated with lower measures of muscle mass, exclusively in men, after adjustment for age and number of drugs per day. Our results indicate sex differences between associations of GDF15 with muscle mass and strength parameters in a cohort of older hospital patients.
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http://dx.doi.org/10.1089/rej.2020.2308DOI Listing
February 2021

Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress.

EMBO Rep 2020 03 6;21(3):e48804. Epub 2020 Feb 6.

Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.

Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress-induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15-dependent daytime-restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress-induced GDF15 in the regulation of systemic energy metabolism.
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http://dx.doi.org/10.15252/embr.201948804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054681PMC
March 2020

Veganism, aging and longevity: new insight into old concepts.

Curr Opin Clin Nutr Metab Care 2020 03;23(2):145-150

Institute of Nutritional Science, University of Potsdam.

Purpose Of Review: Plant-based diets are associated with better health and longevity. Veganism is a strict form of vegetarianism, which has gained increasing attention in recent years. This review will focus on studies addressing mortality and health-span in vegans and vegetarians and discuss possible longevity-enhancing mechanisms.

Recent Findings: Studies in vegans are still limited. Epidemiologic studies consistently show lower disease rates, such as lower incidence of cancer and cardiovascular disease, but mortality rates are comparable with rates in vegetarians and occasional meat eaters. Reasons for following strict vegan diets differ, which may affect diet quality, and thus health and life-span. New insights into some characteristics of veganism, such as protein restriction or restriction in certain amino acids (leucine or methionine) show potentially life-span-enhancing potential. Veganism improves insulin resistance and dyslipidemia and associated abnormalities. Gut microbiota as mediator of dietary impact on host metabolism is more diverse in vegans and has been suggested to be a health-promoting factor. Vegan diets do not fulfill the requirements of children, pregnant women or old individuals who should receive adequate supplements.

Summary: There is substantial evidence that plant-based diets are associated with better health but not necessarily lower mortality rates. The exact mechanisms of health promotion by vegan diets are still not entirely clear but most likely multifactorial. Reasons for and quality of the vegan diet should be assessed in longevity studies.
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http://dx.doi.org/10.1097/MCO.0000000000000625DOI Listing
March 2020

Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice.

Sci Rep 2019 12 27;9(1):20120. Epub 2019 Dec 27.

Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.

Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57Bl/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.
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http://dx.doi.org/10.1038/s41598-019-56922-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934564PMC
December 2019

Mitochondrial uncoupling and longevity - A role for mitokines?

Exp Gerontol 2020 02 28;130:110796. Epub 2019 Nov 28.

German Institute of Human Nutrition in Potsdam Rehbrücke, Nuthetal, Germany.

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.
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http://dx.doi.org/10.1016/j.exger.2019.110796DOI Listing
February 2020

Higher serum levels of fibroblast growth factor 21 in old patients with cachexia.

Nutrition 2019 Jul - Aug;63-64:81-86. Epub 2018 Nov 22.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin and Berlin Institute of Health, Research Group on Geriatrics, Working Group Nutrition and Body Composition, Berlin, Germany; German Institute of Human Nutrition Potsdam - Rehbrücke, Department of Nutrition and Gerontology, Nuthetal, Germany; University of Potsdam, Institute of Nutritional Science, Nuthetal, Germany. Electronic address:

Objective: Fibroblast growth factor (FGF)21 is promptly induced by short fasting in animal models to regulate glucose and fat metabolism. Data on FGF21 in humans are inconsistent and FGF21 has not yet been investigated in old patients with cachexia, a complex syndrome characterized by inflammation and weight loss. The aim of this study was to explore the association of FGF21 with cachexia in old patients compared with their healthy counterparts.

Methods: Serum FGF21 and its inactivating enzyme fibroblast activation protein (FAP)-α were measured with enzyme-linked immunoassays. Cachexia was defined as ≥5% weight loss in the previous 3 mo and concurrent anorexia (Council on Nutrition appetite questionnaire).

Results: We included 103 patients with and without cachexia (76.9 ± 5.2 y of age) and 56 healthy controls (72.9 ± 5.9 y of age). Cachexia was present in 16.5% of patients. These patients had significantly higher total FGF21 levels than controls (952.1 ± 821.3 versus 525.2 ± 560.3 pg/mL; P = 0.012) and the lowest FGF21 levels (293.3 ± 150.9 pg/mL) were found in the control group (global P < 0.001). Although FAP-α did not differ between the three groups (global P = 0.082), bioactive FGF21 was significantly higher in patients with cachexia (global P = 0.002). Risk factor-adjusted regression analyses revealed a significant association between cachexia and total (β = 649.745 pg/mL; P < 0.001) and bioactive FGF21 (β = 393.200 pg/mL; P <0.001), independent of sex, age, and body mass index.

Conclusions: Patients with cachexia exhibited the highest FGF21 levels. Clarification is needed to determine whether this is an adaptive response to nutrient deprivation in disease-related cachexia or whether the increased FGF21 values contribute to the catabolic state.
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http://dx.doi.org/10.1016/j.nut.2018.11.004DOI Listing
September 2020

Low proteasomal activity in fast skeletal muscle fibers is not associated with increased age-related oxidative damage.

Exp Gerontol 2019 03 24;117:45-52. Epub 2018 Oct 24.

Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany; Faculty of Medicine, Department for Biomedicine, University of Porto, 4200-319, Portugal; Institute for Innovation and Health Research (I3S), Aging and Stress Group, R. Alfredo Allen, 4200-135 Porto, Portugal. Electronic address:

The skeletal muscle is a crucial tissue for maintaining whole body homeostasis. Aging seems to have a disruptive effect on skeletal muscle homeostasis including proteostasis. However, how aging specifically impacts slow and fast twitch fiber types remains elusive. Muscle proteostasis is largely maintained by the proteasomal system. Here we characterized the proteasomal system in two different fiber types, using a non-sarcopenic aging model. By analyzing the proteasomal activity and amount, as well as the polyubiquitinated proteins and the level of protein oxidation in Musculus soleus (Sol) and Musculus extensor digitorum longus (EDL), we found that the slow twitch Sol muscle shows an overall higher respiratory and proteasomal activity in young and old animals. However, especially during aging the fast twitch EDL muscle reduces protein oxidation by an increase of antioxidant capacity. Thus, under adaptive non-sarcopenic conditions, the two fibers types seem to have different strategies to avoid age-related changes.
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http://dx.doi.org/10.1016/j.exger.2018.10.018DOI Listing
March 2019

Control of hepatic gluconeogenesis by Argonaute2.

Mol Metab 2018 12 9;18:15-24. Epub 2018 Oct 9.

Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, Berlin, Germany; John Hopkins University, All Children's Hospital, St. Petersburg, Florida, USA. Electronic address:

Objective: The liver performs a central role in regulating energy homeostasis by increasing glucose output during fasting. Recent studies on Argonaute2 (Ago2), a key RNA-binding protein mediating the microRNA pathway, have illustrated its role in adaptive mechanisms according to changes in metabolic demand. Here we sought to characterize the functional role of Ago2 in the liver in the maintenance of systemic glucose homeostasis.

Methods: We first analyzed Ago2 expression in mouse primary hepatocyte cultures after modulating extracellular glucose concentrations and in the presence of activators or inhibitors of glucokinase activity. We then characterized a conditional loss-of-function mouse model of Ago2 in liver for alterations in systemic energy metabolism.

Results: Here we show that Ago2 expression in liver is directly correlated to extracellular glucose concentrations and that modulating glucokinase activity is adequate to affect hepatic Ago2 levels. Conditional deletion of Ago2 in liver resulted in decreased fasting glucose levels in addition to reducing hepatic glucose production. Moreover, loss of Ago2 promoted hepatic expression of AMP-activated protein kinase α1 (AMPKα1) by de-repressing its targeting by miR-148a, an abundant microRNA in the liver. Deletion of Ago2 from hyperglycemic, obese, and insulin-resistant Lep mice reduced both random and fasted blood glucose levels and body weight and improved insulin sensitivity.

Conclusions: These data illustrate a central role for Ago2 in the adaptive response of the liver to fasting. Ago2 mediates the suppression of AMPKα1 by miR-148a, thereby identifying a regulatory link between non-coding RNAs and a key stress regulator in the hepatocyte.
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http://dx.doi.org/10.1016/j.molmet.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308973PMC
December 2018

Author Correction: Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling.

Sci Rep 2018 Jul 24;8(1):11382. Epub 2018 Jul 24.

Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, 14558, Nuthetal, Germany.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-29610-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056490PMC
July 2018

Insulin sensitivity linked skeletal muscle Nr4a1 DNA methylation is programmed by the maternal diet and modulated by voluntary exercise in mice.

J Nutr Biochem 2018 07 21;57:86-92. Epub 2018 Mar 21.

Department Physiology of Energy Metabolism, German Institute of Human Nutrition in Potsdam Rehbruecke, 14558 Nuthetal, Germany.

Perinatal maternal high-fat consumption is known to increase the obesity and type 2 diabetes susceptibility and to impair exercise performance in the offspring. We hypothesize that epigenetic modifications in the skeletal muscle are partly responsible for this phenotype. To detect skeletal muscle genes affected by maternal nutrition, male offspring of low-fat (LF) and high-fat (HF) diet fed dams (BL6 mice) received LF diet upon weaning and were sacrificed at 6 or 25 weeks of age. Gene expression of Musculus quadriceps was investigated by microarray analysis revealing an up-regulation of the nuclear receptor Nr4a1 by maternal HF feeding. This was accompanied by promoter hypomethylation of CpG which correlated with increased Nr4a1 gene expression at both ages. Offspring voluntary exercise training (by supplying running wheels from 7 to 25 weeks of age) normalized Nr4a1 methylation and gene expression respectively, and ameliorated the negative effects of maternal HF feeding on insulin sensitivity. Overall, Nr4a1 gene expression in skeletal muscle correlated with higher insulin levels during an oral glucose tolerance test and could, therefore, be involved in programming type 2 diabetes susceptibility in offspring exposed to perinatal high fat diet.
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http://dx.doi.org/10.1016/j.jnutbio.2018.03.015DOI Listing
July 2018

Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling.

Sci Rep 2018 02 5;8(1):2446. Epub 2018 Feb 5.

Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, 14558, Nuthetal, Germany.

Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing. However, salutary effects in response to mild mitochondrial perturbations have been reported in multiple organisms, whereas molecular regulators of cell-autonomous stress responses remain elusive. We addressed this question by asking whether the nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor and master regulator of cellular redox status is involved in adaptive physiological responses including muscle mitohormesis. Using a transgenic mouse model with skeletal muscle-specific mitochondrial uncoupling and oxidative phosphorylation (OXPHOS) inefficiency (UCP1-transgenic, TG) we show that additional genetic ablation of Nrf2 abolishes an adaptive muscle NAD(P)H quinone dehydrogenase 1 (NQO1) and catalase induction. Deficiency of Nrf2 also leads to decreased mitochondrial respiratory performance although muscle functional integrity, fiber-type profile and mitochondrial biogenesis were not significantly altered. Importantly, Nrf2 ablation did not abolish the induction of key genes and proteins of muscle integrated stress response including the serine, one-carbon cycle, and glycine synthesis (SOG) pathway in TG mice while further increasing glutathione peroxidase (GPX) activity linked to increased GPX1 protein levels. Conclusively, our results tune down the functions controlled by Nrf2 in muscle mitohormesis and oxidative stress defense during mitochondrial OXPHOS inefficiency.
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http://dx.doi.org/10.1038/s41598-018-20901-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799251PMC
February 2018

Reply to TM Venäläinen et al.

Am J Clin Nutr 2017 09;106(3):954-955

From the Department of Physiology of Energy Metabolism, German Institute of Human Nutrition in Potsdam Rehbruecke, Nuthetal, Germany (SS; SK; KW, e-mail:

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http://dx.doi.org/10.3945/ajcn.117.162594DOI Listing
September 2017

Short-chain fatty acids and inulin, but not guar gum, prevent diet-induced obesity and insulin resistance through differential mechanisms in mice.

Sci Rep 2017 07 21;7(1):6109. Epub 2017 Jul 21.

Department Physiology of Energy Metabolism, German Institute of Human Nutrition in Potsdam Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.

The role of dietary fibre and short-chain fatty acids (SCFA) in obesity development is controversially discussed. Here, we investigated how various types of dietary fibre and different SCFA ratios affect metabolic syndrome-related disorders. Male mice (B6) were fed high-fat diets supplemented with dietary fibres (either cellulose, inulin or guar gum) or different Ac:Pr ratios (high acetate (HAc) or propionate (HPr)) for 30 weeks. Body-fat gain and insulin resistance were greatly reduced by inulin, but not by guar gum, and completely prevented by SCFA supplementation. Only inulin and HAc increased body temperature, possibly by the induction of beige/browning markers in WAT. In addition, inulin and SCFA lowered hepatic triglycerides and improved insulin sensitivity. Both, inulin and HAc reduced hepatic fatty acid uptake, while only inulin enhanced mitochondrial capacity and only HAc suppressed lipogenesis in liver. Interestingly, HPr was accompanied by the induction of Nrg4 in BAT. Fermentable fibre supplementation increased the abundance of bifidobacteria; B. animalis was particularly stimulated by inulin and B. pseudolongum by guar gum. We conclude that in contrast to guar gum, inulin and SCFA prevent the onset of diet-induced weight gain and hepatic steatosis by different mechanisms on liver and adipose tissue metabolism.
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http://dx.doi.org/10.1038/s41598-017-06447-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522422PMC
July 2017

Odd-chain fatty acids as a biomarker for dietary fiber intake: a novel pathway for endogenous production from propionate.

Am J Clin Nutr 2017 06 19;105(6):1544-1551. Epub 2017 Apr 19.

Departments of Physiology of Energy Metabolism.

The risk of type 2 diabetes is inversely correlated with plasma concentrations of odd-chain fatty acids [OCFAs; pentadecanoic acid (15:0) and heptadecanoic acid (17:0)], which are considered as biomarkers for dairy fat intake in humans. However, rodent studies suggest that OCFAs are synthesized endogenously from gut-derived propionate. Propionate increases with dietary fiber consumption and has been shown to improve insulin sensitivity. We hypothesized that OCFAs are produced in humans from dietary fibers by a novel endogenous pathway. In a randomized, double-blind crossover study, 16 healthy individuals were supplemented with cellulose (30 g/d), inulin (30 g/d), or propionate (6 g/d) for 7 d. In addition, human hepatoma cells were incubated with different propionate concentrations. OCFAs were determined in plasma phospholipids and hepatoma cells by gas chromatography. Cellulose did not affect plasma OCFA levels, whereas inulin and propionate increased pentadecanoic acid by ∼17% ( < 0.05) and 13% ( = 0.05), respectively. The effect on heptadecanoic acid was even more pronounced, because it was elevated in almost all participants by inulin (11%; < 0.01) and propionate (13%; < 0.001). Furthermore, cell culture experiments showed a positive association between propionate and OCFA levels ( = 0.99, < 0.0001), whereas palmitate (16:0) was negatively correlated ( = 0.83, = 0.004). Our data show that gut-derived propionate is used for the hepatic synthesis of OCFAs in humans. The association of OCFAs with a decreased risk of type 2 diabetes may therefore also relate to dietary fiber intake and not only dairy fat. This trial was registered at www.germanctr.de as DRKS00010121.
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http://dx.doi.org/10.3945/ajcn.117.152702DOI Listing
June 2017

Beneficial effects of exercise on offspring obesity and insulin resistance are reduced by maternal high-fat diet.

PLoS One 2017 24;12(2):e0173076. Epub 2017 Feb 24.

Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.

Scope: We investigated the long-term effects of maternal high-fat consumption and post-weaning exercise on offspring obesity susceptibility and insulin resistance.

Methods: C57BL/6J dams were fed either a high-fat (HFD, 40% kcal fat) or low-fat (LFD, 10% kcal fat) semi-synthetic diet during pregnancy and lactation. After weaning, male offspring of both maternal diet groups (mLFD; mHFD) received a LFD. At week 7, half of the mice got access to a running wheel (+RW) as voluntary exercise training. To induce obesity, all offspring groups (mLFD +/-RW and mHFD +/-RW) received HFD from week 15 until week 25.

Results: Compared to mLFD, mHFD offspring were more prone to HFD-induced body fat gain and exhibited an increased liver mass which was not due to increased hepatic triglyceride levels. RW improved the endurance capacity in mLFD, but not in mHFD offspring. Additionally, mHFD offspring +RW exhibited higher plasma insulin levels during glucose tolerance test and an elevated basal pancreatic insulin production compared to mLFD offspring.

Conclusion: Taken together, maternal HFD reduced offspring responsiveness to the beneficial effects of voluntary exercise training regarding the improvement of endurance capacity, reduction of fat mass gain, and amelioration of HFD-induced insulin resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173076PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325607PMC
August 2017

Targeted mitochondrial uncoupling beyond UCP1 - The fine line between death and metabolic health.

Biochimie 2017 Mar 2;134:77-85. Epub 2016 Dec 2.

Research Group Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Germany.

In the early 1930s, the chemical uncoupling agent 2,4-dinitrophenol (DNP) was promoted for the very first time as a powerful and effective weight loss pill but quickly withdrawn from the market due to its lack of tissue-selectivity with resulting dangerous side effects, including hyperthermia and death. Today, novel mitochondria- or tissue-targeted chemical uncouplers with higher safety and therapeutic values are under investigation in order to tackle obesity, diabetes and fatty liver disease. Moreover, in the past 20 years, transgenic mouse models were generated to understand the molecular and metabolic consequences of targeted uncoupling, expressing functional uncoupling protein 1 (UCP1) ectopically in white adipose tissue or skeletal muscle. Similar to the action of chemical mitochondrial uncouplers, UCP1 protein dissipates the proton gradient across the inner mitochondrial membrane, thus allowing maximum activity of the respiratory chain and compensatory increase in oxygen consumption, uncoupled from ATP synthesis. Consequently, targeted mitochondrial uncoupling in adipose tissue and skeletal muscle of UCP1-transgenic mice increased substrate metabolism and ameliorates obesity, hypertriglyceridemia and insulin resistance. Further, muscle-specific decrease in mitochondrial efficiency promotes a cell-autonomous and cell-non-autonomous adaptive metabolic remodeling with increased oxidative stress tolerance. This review provides an overview of novel chemical uncouplers as well as the metabolic consequences and adaptive processes of targeted mitochondrial uncoupling on metabolic health and survival.
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http://dx.doi.org/10.1016/j.biochi.2016.11.013DOI Listing
March 2017

Isocaloric Diets High in Animal or Plant Protein Reduce Liver Fat and Inflammation in Individuals With Type 2 Diabetes.

Gastroenterology 2017 02 17;152(3):571-585.e8. Epub 2016 Oct 17.

German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, Germany; Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is associated with increased risk of hepatic, cardiovascular, and metabolic diseases. High-protein diets, rich in methionine and branched chain amino acids (BCAAs), apparently reduce liver fat, but can induce insulin resistance. We investigated the effects of diets high in animal protein (AP) vs plant protein (PP), which differ in levels of methionine and BCAAs, in patients with type 2 diabetes and NAFLD. We examined levels of liver fat, lipogenic indices, markers of inflammation, serum levels of fibroblast growth factor 21 (FGF21), and activation of signaling pathways in adipose tissue.

Methods: We performed a prospective study of individuals with type 2 diabetes and NAFLD at a tertiary medical center in Germany from June 2013 through March 2015. We analyzed data from 37 subjects placed on a diet high in AP (rich in meat and dairy foods; n = 18) or PP (mainly legume protein; n = 19) without calorie restriction for 6 weeks. The diets were isocaloric with the same macronutrient composition (30% protein, 40% carbohydrates, and 30% fat). Participants were examined at the start of the study and after the 6-week diet period for body mass index, body composition, hip circumference, resting energy expenditure, and respiratory quotient. Body fat and intrahepatic fat were detected by magnetic resonance imaging and spectroscopy, respectively. Levels of glucose, insulin, liver enzymes, and inflammation markers, as well as individual free fatty acids and free amino acids, were measured in collected blood samples. Hyperinsulinemic euglycemic clamps were performed to determine whole-body insulin sensitivity. Subcutaneous adipose tissue samples were collected and analyzed for gene expression patterns and phosphorylation of signaling proteins.

Results: Postprandial levels of BCAAs and methionine were significantly higher in subjects on the AP vs the PP diet. The AP and PP diets each reduced liver fat by 36%-48% within 6 weeks (for AP diet P = .0002; for PP diet P = .001). These reductions were unrelated to change in body weight, but correlated with down-regulation of lipolysis and lipogenic indices. Serum level of FGF21 decreased by 50% in each group (for AP diet P < .0002; for PP diet P < .0002); decrease in FGF21 correlated with loss of hepatic fat. In gene expression analyses of adipose tissue, expression of the FGF21 receptor cofactor β-klotho was associated with reduced expression of genes encoding lipolytic and lipogenic proteins. In patients on each diet, levels of hepatic enzymes and markers of inflammation decreased, insulin sensitivity increased, and serum level of keratin 18 decreased.

Conclusions: In a prospective study of patients with type 2 diabetes, we found diets high in protein (either animal or plant) significantly reduced liver fat independently of body weight, and reduced markers of insulin resistance and hepatic necroinflammation. The diets appear to mediate these changes via lipolytic and lipogenic pathways in adipose tissue. Negative effects of BCAA or methionine were not detectable. FGF21 level appears to be a marker of metabolic improvement. ClinicalTrials.gov ID NCT02402985.
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http://dx.doi.org/10.1053/j.gastro.2016.10.007DOI Listing
February 2017

Importance of propionate for the repression of hepatic lipogenesis and improvement of insulin sensitivity in high-fat diet-induced obesity.

Mol Nutr Food Res 2016 12 30;60(12):2611-2621. Epub 2016 Aug 30.

Research Group Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam Rehbruecke, Nuthetal, Germany.

Scope: The SCFA acetate (Ac) and propionate (Pr) are major fermentation products of dietary fibers and provide additional energy to the host. We investigated short- and long-term effects of dietary Ac and Pr supplementation on diet-induced obesity and hepatic lipid metabolism.

Methods And Results: C3H/HeOuJ mice received high-fat (HF) diets supplemented with 5% SCFA in different Ac:Pr ratios, a high acetate (HF-HAc; 2.5:1 Ac:Pr) or high Pr ratio (HF-HPr; 1:2.5 Ac:Pr) for 6 or 22 weeks. Control diets (low-fat (LF), HF) contained no SCFA. SCFA did not affect body composition but reduced hepatic gene and protein expression of lipogenic enzymes leading to a reduced hepatic triglyceride concentration after 22 weeks in HF-HPr mice. Analysis of long-chain fatty acid composition (liver and plasma phospholipids) showed that supplementation of both ratios led to a lower ω6:ω3 ratio. Pr directly led to increased odd-chain fatty acid (C15:0, C17:0) formation as confirmed in vitro using HepG2 cells. Remarkably, plasma C15:0 was correlated with the attenuation of HF diet-induced insulin resistance.

Conclusion: Dependent on the Ac:Pr ratio, especially odd-chain fatty acid formation and insulin sensitivity are differentially affected, indicating the importance of Pr.
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http://dx.doi.org/10.1002/mnfr.201600305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215627PMC
December 2016

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action.

Mol Metab 2016 Feb 24;5(2):79-90. Epub 2015 Nov 24.

Research Group Physiology of Energy Metabolism, German Institute of Human Nutrition, Nuthetal, 14558, Germany.

Objective: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood.

Methods: We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21(-/-)) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions.

Results: Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPR(mt)) and amino acid biosynthetic pathways did not require the presence of FGF21.

Conclusions: Here we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.
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http://dx.doi.org/10.1016/j.molmet.2015.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735627PMC
February 2016

Regulation of myokine expression: Role of exercise and cellular stress.

Free Radic Biol Med 2016 09 17;98:78-89. Epub 2016 Feb 17.

Research Group Physiology of Energy Metabolism, German Institute of Human Nutrition in Potsdam Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. Electronic address:

Exercise training is well known to improve physical fitness and to combat chronic diseases and aging related disorders. Part of this is thought to be mediated by myokines, muscle derived secretory proteins (mainly cytokines) that elicit auto/paracrine but also endocrine effects on organs such as liver, adipose tissue, and bone. Today, several hundred potential myokines have been identified most of them not exclusive to muscle cells. Strenuous exercise is associated with increased production of free radicals and reactive oxidant species (ROS) as well as endoplasmic reticulum (ER)-stress which at an excessive level can lead to muscle damage and cell death. On the other hand, transient elevations in oxidative and ER-stress are thought to be necessary for adaptive improvements by regular exercise through a hormesis action termed mitohormesis since mitochondria are essential for the generation of energy and tightly connected to ER- and oxidative stress. Exercise induced myokines have been identified by various in vivo and in vitro approaches and accumulating evidence suggests that ROS and ER-stress linked pathways are involved in myokine induction. For example, interleukin (IL)-6, the prototypic exercise myokine is also induced by oxidative and ER-stress. Exercise induced expression of some myokines such as irisin and meteorin-like is linked to the transcription factor PGC-1α and apparently not related to ER-stress whereas typical ER-stress induced cytokines such as FGF-21 and GDF-15 are not exercise myokines under normal physiological conditions. Recent technological advances have led to the identification of numerous potential new myokines but for most of them regulation by oxidative and ER-stress still needs to be unraveled.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.02.018DOI Listing
September 2016
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