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      The FGF21 response to fructose predicts metabolic health and persists after bariatric surgery in obese humans

      research-article
      1 , 12 , 1 , 12 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 1 ,
      Molecular Metabolism
      Elsevier
      Fructose, FGF21, Insulin resistance, Hyperinsulinemic-euglycemic clamp, Obesity, Translational study, AUC, area under the curve, ChREBP, carbohydrate response element-binding protein, EGP, endogenous glucose production, FFA, free fatty acid, FGF21, fibroblast growth factor 21, GLP1, glucagon-like peptide 1, IQR, interquartile range, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, Ra, rate of appearance, Rd, rate of disappearance, SD, standard deviation

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          Abstract

          Objective

          Fructose consumption has been implicated in the development of obesity and insulin resistance. Emerging evidence shows that fibroblast growth factor 21 (FGF21) has beneficial effects on glucose, lipid, and energy metabolism and may also mediate an adaptive response to fructose ingestion. Fructose acutely stimulates circulating FGF21 consistent with a hormonal response. We aimed to evaluate whether fructose-induced FGF21 secretion is linked to metabolic outcomes in obese humans before and after bariatric surgery-induced weight loss.

          Methods

          We recruited 40 Roux-en-Y gastric bypass patients and assessed the serum FGF21 response to fructose (75-g fructose tolerance test) and basal and insulin-mediated glucose and lipid fluxes during a 2-step hyperinsulinemic-euglycemic clamp with infusion of [6,6- 2H 2] glucose and [1,1,2,3,3- 2H 5] glycerol. Liver biopsies were obtained during bariatric surgery. Nineteen subjects underwent the same assessments at 1-year follow-up.

          Results

          Serum FGF21 increased 3-fold at 120 min after fructose ingestion and returned to basal levels at 300 min. Neither basal FGF21 nor the fructose-FGF21 response correlated with liver fat content or liver histopathology, but increased levels were associated with elevated endogenous glucose production, increased lipolysis, and peripheral/muscle insulin resistance. At 1-year follow-up, subjects had lost 28 ± 6% of body weight and improved in all metabolic outcomes, but fructose-stimulated FGF21 dynamics did not markedly differ from the pre-surgical state. The association between increased basal and stimulated FGF21 levels with poor metabolic health was no longer present after weight loss.

          Conclusions

          Fructose ingestion in obese humans stimulates FGF21 secretion, and this response is related to systemic metabolism. Further studies are needed to establish if FGF21 signaling is (patho)physiologically involved in fructose metabolism and metabolic health.

          Highlights

          • High fructose consumption may contribute to metabolic disease.

          • Fructose ingestion acutely stimulates FGF21 secretion in obese humans.

          • Higher FGF21 levels are associated with poor metabolic health.

          • The FGF21 response to fructose persists after bariatric surgery-induced weight loss.

          • The role of FGF21 signaling in fructose metabolism needs further investigation.

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          Most cited references53

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          Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.

          Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.
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            Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

            OBJECTIVE—Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model. RESEARCH DESIGN AND METHODS—DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS—FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity. CONCLUSIONS—FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.
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              Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.

              Obesity is a major epidemic, but its causes are still unclear. In this article, we investigate the relation between the intake of high-fructose corn syrup (HFCS) and the development of obesity. We analyzed food consumption patterns by using US Department of Agriculture food consumption tables from 1967 to 2000. The consumption of HFCS increased > 1000% between 1970 and 1990, far exceeding the changes in intake of any other food or food group. HFCS now represents > 40% of caloric sweeteners added to foods and beverages and is the sole caloric sweetener in soft drinks in the United States. Our most conservative estimate of the consumption of HFCS indicates a daily average of 132 kcal for all Americans aged > or = 2 y, and the top 20% of consumers of caloric sweeteners ingest 316 kcal from HFCS/d. The increased use of HFCS in the United States mirrors the rapid increase in obesity. The digestion, absorption, and metabolism of fructose differ from those of glucose. Hepatic metabolism of fructose favors de novo lipogenesis. In addition, unlike glucose, fructose does not stimulate insulin secretion or enhance leptin production. Because insulin and leptin act as key afferent signals in the regulation of food intake and body weight, this suggests that dietary fructose may contribute to increased energy intake and weight gain. Furthermore, calorically sweetened beverages may enhance caloric overconsumption. Thus, the increase in consumption of HFCS has a temporal relation to the epidemic of obesity, and the overconsumption of HFCS in calorically sweetened beverages may play a role in the epidemic of obesity.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                04 September 2017
                November 2017
                04 September 2017
                : 6
                : 11
                : 1493-1502
                Affiliations
                [1 ]Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
                [2 ]Department of Surgery, Red Cross Hospital, Vondellaan 13, 1942LE Beverwijk, The Netherlands
                [3 ]Department of Surgery, OLVG, Postbus 9243, 1006AE Amsterdam, The Netherlands
                [4 ]Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
                [5 ]Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
                [6 ]Department of Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
                [7 ]Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
                [8 ]Department of Internal Medicine, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands
                [9 ]Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands
                [10 ]Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Center for Life Sciences, Boston, MA 02215, USA
                [11 ]Division of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine, 300 N. Duke Street, Carmichael Building, Durham, NC 27701, USA
                Author notes
                []Corresponding author. Department of Endocrinology and Metabolism (F5-167), Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. Fax: +31 206917682.Department of Endocrinology and Metabolism (F5-167)Academic Medical CenterMeibergdreef 9Amsterdam1105AZThe Netherlands m.j.serlie@ 123456amc.nl
                [12]

                Kasper W. ter Horst and Pim W. Gilijamse contributed equally to this work.

                Article
                S2212-8778(17)30610-5
                10.1016/j.molmet.2017.08.014
                5681276
                29107295
                b0f6dbec-97e0-403f-a671-011d98b36c95
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 10 August 2017
                : 24 August 2017
                : 30 August 2017
                Categories
                Original Article

                fructose,fgf21,insulin resistance,hyperinsulinemic-euglycemic clamp,obesity,translational study,auc, area under the curve,chrebp, carbohydrate response element-binding protein,egp, endogenous glucose production,ffa, free fatty acid,fgf21, fibroblast growth factor 21,glp1, glucagon-like peptide 1,iqr, interquartile range,nafld, non-alcoholic fatty liver disease,nash, non-alcoholic steatohepatitis,ra, rate of appearance,rd, rate of disappearance,sd, standard deviation

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