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Purpose: The gut microbiome is associated with obesity, mainly mediated by bacteria-produced short-chain fatty acids (SCFAs). It is unknown how SCFA concentrations are associated among the phenotypes metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obese/overweight (MHO), and metabolically unhealthy obese/overweight (MUO). We compared plasma and fecal SCFA concentrations among adult women categorized according to the metabolic phenotypes mentioned above and examined associations between SCFA and adiposity and components of energy and glucose homeostasis. Methods: This was a cross-sectional study involving 111 participants. Body composition was assessed by DEXA. Energy and glycemic homeostasis were assessed by the standard mixed-meal tolerance test coupled with indirect calorimetry. SCFAs were quantified by gas chromatography and mass spectrometry. Results: Only plasma propionate was increased in the MHNW phenotype compared to the MHO and MUO phenotypes [p

The incidence of cardiovascular diseases and metabolic disorders has increased worldwide. Clinical and experimental research has shown that the consumption of ω-3 FAs can be beneficial to metabolism in several ways, as they can act on metabolic pathways. Our objective was to evaluate the effect of treatment with linseed oil, a vegetable oil rich in alpha-linolenic acid, and EPA and DHA in different proportions (3:1 EPA:DHA, and 1:3 EPA:DHA), on the metabolic disorders induced by a high-fat diet (20 % lipids) in rats for 2 weeks, after 18 weeks of consumption of a high-fat diet. In 18 weeks, the high-fat diet increased blood glucose, systolic blood pressure, triglyceride concentration in the liver and adipose tissue, and impaired insulin sensibility without interfering in the weight of the animals. All treatments were effective in reducing the deposition of hepatic type III collagen, the proportion of ω-6/ω-3 in the liver and WAT (white adipose tissue), the proportion of area/number of adipocytes, and the gene expression of the ACC, FAS, and CPT1 enzymes. In addition, treatment with EPA and DHA reduced blood glucose, serum TNF-α concentration, amount of liver fat, degree of microsteatosis and type I collagen deposition in the liver, deposition of type I and III collagen in TA, gene expression of the transcription factor SREBP-1c, and increased hepatic binucleation. EPA in major proportion was more effective in reducing the area of adipocytes, hepatic triglyceride concentration, PPAR-α expression, and WAT fat weight. DHA in a major proportion reduced the concentration of MCP1 in WAT. LO treatment did not have any isolated effects. We concluded that EPA and DHA were more effective in treating metabolic damage than treatment with LO, leading to a more favorable metabolic profile.

The maintenance of mitochondrial activity in hypothalamic neurons is determinant to the control of energy homeostasis in mammals. Disturbs in the mitochondrial proteostasis can trigger the mitonuclear imbalance and mitochondrial unfolded protein response (UPRmt) to guarantee the mitochondrial integrity and function. However, the role of mitonuclear imbalance and UPRmt in hypothalamic cells are unclear. Combining the transcriptomic analyses from BXD mice database and in vivo experiments, we demonstrated that physical training alters the mitochondrial proteostasis in the hypothalamus of C57BL/6J mice. This physical training elicited the mitonuclear protein imbalance, increasing the mtCO-1/Atp5a ratio, which was accompanied by high levels of UPRmt markers in the hypothalamus. Also, physical training increased the maximum mitochondrial respiratory capacity in the brain. Interestingly, the transcriptomic analysis across several strains of the isogenic BXD mice revealed that hypothalamic mitochondrial DNA-encoded genes were negatively correlated with body weight and several genes related to the orexigenic response. As expected, physical training reduced body weight and food intake. Interestingly, we found an abundance of mt-CO1, a mitochondrial DNA-encoded protein, in NPY-producing neurons in the lateral hypothalamus nucleus of exercised mice. Collectively, our data demonstrated that physical training altered the mitochondrial proteostasis and induced the mitonuclear protein imbalance and UPRmt in hypothalamic cells.

Obesity is closely related to insulin resistance and type 2 diabetes genesis. The liver is a key organ to glucose homeostasis since insulin resistance in this organ increases hepatic glucose production (HGP) and fasting hyperglycemia. The protein-tyrosine phosphatase 1B (PTP1B) may dephosphorylate the IR and IRS, contributing to insulin resistance in this organ. Aerobic exercise is a great strategy to increase insulin action in the liver by reducing the PTP1B content. In contrast, no study has shown the direct effects of strength training on the hepatic metabolism of PTP1B. Therefore, this study aims to investigate the effects of short-term strength exercise (STSE) on hepatic insulin sensitivity and PTP1B content in obese mice, regardless of body weight change. To achieve this goal, obese Swiss mice were submitted to a strength exercise protocol lasting 15 days. The results showed that STSE increased Akt phosphorylation in the liver and enhanced the control of HGP during the pyruvate tolerance test. Furthermore, sedentary obese animals increased PTP1B content and decreased IRS-1/2 tyrosine phosphorylation, however, STSE was able to reverse this scenario. Therefore, we conclude that STSE is an important strategy to improve the hepatic insulin sensitivity and HGP by reducing the PTP1B content in the liver of obese mice, regardless of changes in body weight.

Background The brown adipose tissue (BAT) is a potential target for the treatment of obesity and metabolic disorders. Its activation by cold exposure or adrenergic drugs can increase systemic insulin sensitivity and improve lipid metabolism; however, little is known about the effects of specific dietary components on BAT activity. Objectives We asked if a short-term (4 weeks) dietary intervention with olive oil could modify BAT activity in lean and overweight/obese volunteers. Design This was a 4-week open clinical trial in which all participants underwent a dietary intervention with extra-virgin olive oil supplementation. As the initial intake of olive oil was controlled all the participants were controls of themselves. Results The intervention resulted in significant increase in blood monounsaturated fatty acid levels, which was accompanied by increased BAT activity in lean but not in overweight/obese volunteers. In the lean group, an increase in leptin was detected after the intervention, and low leptin values at the beginning of the study were predictive of greater BAT activity after intervention. In addition, increase in leptin concentration was associated with increased BAT activity. Three known endogenous mediators of BAT activity, secretin, fibroblast growth factor 21 (FGF21), and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were increased by intervention in lean, whereas only secretin and FGF21 were increased in subjects with excessive weight. Conclusion This study provides clinical evidence for the impact of monounsaturated fatty acids on BAT activity and an advance in the understanding of the beneficial health effects of olive oil.

Obesity is linked to a reduction in the control of hepatic glucose production, which is the primary mechanism related to fasting hyperglycemia and the development of type 2 diabetes mellitus (T2DM). The main system involved in hepatic gluconeogenesis synthesis is controlled by pyruvate carboxylase (PC), which increases in obesity conditions. Recently, we showed that short-term strength training is an important tool against obesity-induced hyperglycemia. As aerobic exercise can reduce the hepatic PC content of obese animals, we hypothesized that strength exercise can also decrease this gluconeogenic enzyme. Therefore, this study investigated whether the metabolic benefits promoted by short-term strength training are related to changes in hepatic PC content. Swiss mice were divided into three groups: lean control (Ctl), obese sedentary (ObS), and obese short-term strength training (STST). The STST protocol was performed through one session/day for 15 days. The obese exercised animals had reduced hyperglycemia and insulin resistance. These results were related to better control of hepatic glucose production and hepatic insulin sensitivity. Our bioinformatics analysis showed that hepatic PC mRNA levels have positive correlations with glucose levels and adiposity, and negative correlations with locomotor activity and muscle mass. We also found that hepatic mRNA levels are related to lipogenic markers in the liver. Finally, we observed that the obese animals had an increased hepatic PC level; however, STST was efficient in reducing its amount. In conclusion, we provide insights into new biomolecular mechanisms by showing how STST is an efficient tool against obesity-related hyperglycemia and T2DM, even without body weight changes.

Introduction: Many studies report that environmental factors occurring in childhood may modulate the composition of the gut microbiota in adulthood, which in turn, produces short chain fatty acids (SCFA) with metabolic effects on inflammatory cascades associated with glycemic homeostasis. Objective: This study aims to analyze associations between type of delivery (vaginal/cesarean section), type of breast-feeding (maternal/artificial) and solid food introduction (start and quality) with fecal SCFA concentrations in women. Method: A cross-sectional study including 106 women, 28±5 years old and BMI 25±5 kg/m2, a questionnaire regarding from birth until the first year of life. For quantification of acetate, butyrate and propionate it was used gas chromatography-mass spectrometry in fecal samples. Results: Of the women surveyed 63% were cesarean delivered and 93% received maternal breast milk at some point. There was no correlation between SCFA concentration and type of delivery (p>0.05). Positive correlation was found between breastfeeding time and butyrate (r=0.24; p=0.02), there was a tendency with propionate (r=0.20; p=0.06). There was no correlation between time received infant formula and SCFA. There was a tendency of correlation between butyrate and beginning of cow’s milk intake (r=0.194; p=0.052). Age at solid food introduction correlates with propionate (r=0.22; p=0.026) and butyrate (r=0.25; p=0.012), and report a tendency with the acetate (r=0.18; p=0.07). In the first year of life, individuals who prefer salty crackers and pasta/potatoes had less concentration of propionate and acetate, respectively (p=0.026). Conclusion: The type of delivery was not associated with SCFA, but there was a favorable association with prolonged breastfeeding, late beginning of cow’s milk intake, introduction of solids starting after 6 months of age and lower intake of refined cereals. Disclosure M.G. Barbosa: None. I. Solar: None. R.G. Freitas: None. F.B. Ribeiro: None. C.O. Ramos: None. M.R. Sant’Ana: None. A.S. Hanada: None. N.S.K. Crouchan: None. C.M. Xavier: None. B.G. Neto: None. L.G.D. Folchetti: None. I.T. Silva: None. B. Almeida-Pititto: None. S.G. Ferreira-Vivolo: None. A.J. Vasques: None. Funding São Paulo Research Foundation (2017/10185-9, 2019/05450-0)

Background The consumption of nuts and edible seeds is associated with the improvement of the metabolic profile and reduction of cardiovascular diseases. However, the effects of its subproducts, such as oil, are still poorly studied. This study aimed to evaluate the effect of the baru almond oil supplementation on inflammation, oxidative stress, body composition, lipid profile, and plasma fatty acids of hemodialysis patients. Methods In a randomized, double-blind, 12-week placebo-controlled clinical study, hemodialysis patients were supplemented with 5 g of baru oil (BG, n = 17) or 5 g of mineral oil (placebo, BP, n = 12). Body composition, renal function, ultra-sensitive C-reactive protein (us-CRP), oxidative stress, plasma fatty acids, and lipid profile were analysed before and after the intervention. Results Patients were aged 50.5 ± 2.2 years and the average time of dialyses was 52,1 ± 42,6 months. The BG decreased us-CRP concentration compared to PG (-1.2 ± 0.2 vs. + 0.8 ± 0.2 mg / L,d = 0.88; p = 0.01). Baru almond oil supplementation was not effective in improving body composition, lipid profile, and oxidative stress. Conclusion Baru almond oil supplementation decreased us-CRP concentration in patients with chronic kidney disease under hemodialysis treatment.

The chronic and low-grade inflammation induced by obesity seem to be the “first hit” to retinopathy associated to diabetes type 2. Herein, we hypothesized that omega-3 fatty acids from flaxseed oil enriched diet disrupt the pro-inflammatory status in the retina, protecting against retinopathy development. For eight weeks under a high-fat diet (HF), several physiological parameters were monitored to follow the metabolic homeostasis disruption. After this period, mice were treated with a HF substituted in part of lard by flaxseed oil (FS) for another eight weeks. Food behavior, weight gain, glucose and insulin sensitivity, electroretinography, RT-qPCR and western blots were carried out. The HF was able to induce a pro-inflammatory background in the retina, changing IL1β and TNFα. VEGF, a master piece of retinopathy, had early onset increased also induced by HF. The FS-diet was able to decrease inflammation and retinopathy and improved retinal electro stimuli compared to HF group. GPR120 and GPR40 (G Protein-Coupled Receptors 120 and 40), an omega-3 fatty acid receptors, were detected in the retina for the first time. FS-diet modulated the gene expression and protein content of these receptors. Thus, unsaturated fatty acids protect the retina from diabetes type 2 mice model from disease progression.

Made available in DSpace on 2022-04-28T19:47:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-15 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Hepatic steatosis is directly associated with hepatic inflammation and insulin resistance, which is correlated with hyperglycemia and type 2 diabetes mellitus (T2DM). Aerobic and strength training have been pointed out as efficient strategies against hepatic steatosis. However, little is known about the effects of the combination of those two protocols on hepatic steatosis. Therefore, this study aimed to evaluate the impact of short-term combined training (STCT) on glucose homeostasis and in the synthesis and oxidation of fat in the liver of obesity-induced mice with hepatic steatosis. Swiss mice were distributed into three groups: control lean (CTL), sedentary obese (OB), and combined training obese (CTO). The CTO group performed the STCT protocol, which consisted of strength and aerobic exercises in the same session. The protocol lasted seven days. The CTO group reduced the glucose levels and fatty liver when compared to the OB group. Interestingly, these results were observed even without reductions in body adiposity. CTO group also showed increased hepatic insulin sensitivity, with lower hepatic glucose production (HGP). STCT reduced the expression of the lipogenic genes Fasn and Scd1 and hepatic inflammation, as well as increased the ACC phosphorylation and the oxidative genes Cpt1a and Ppara, reverting the complications caused by obesity. Since this protocol increased lipid oxidation and reduced hepatic lipogenesis, regardless of body fat mass decrease, it can be considered an effective non-pharmacological strategy for the treatment of hepatic steatosis. Exercise Cell Biology Lab Faculty of Applied Sciences University of Campinas Laboratory of Nutritional Genomics Faculty of Applied Sciences University of Campinas Motricity Sciences Institute of Biosciences São Paulo State University Julio de Mesquita Filho Multidisciplinary Laboratory of Food and Health Faculty of Applied Sciences University of Campinas School of Physical Education and Sport of Ribeirão Preto University of São Paulo (USP) Postgraduate Program in Rehabilitation and Functional Performance Ribeirão Preto Medical School USP Laboratory of Molecular Biology of Exercise Faculty of Applied Sciences University of Campinas Motricity Sciences Institute of Biosciences São Paulo State University Julio de Mesquita Filho FAPESP: 2015/07199-2 FAPESP: 2016/12569-6 FAPESP: 2016/24406-4

The present study evaluated the effects of exercise training on pyruvate carboxylase protein (PCB) levels in hepatic tissue and glucose homeostasis control in obese mice. Swiss mice were distributed into three groups: control mice (CTL), fed a standard rodent chow; diet-induced obesity (DIO), fed an obesity-inducing diet; and a third group, which also received an obesity-inducing diet, but was subjected to an exercise training protocol (DIO + EXE). Protocol training was carried out for 1 h/d, 5 d/wk, for 8 weeks, performed at an intensity of 60% of exhaustion velocity. An insulin tolerance test (ITT) was performed in the last experimental week. Twenty-four hours after the last physical exercise session, the animals were euthanized and the liver was harvested for molecular analysis. Firstly, DIO mice showed increased epididymal fat and serum glucose and these results were accompanied by increased PCB and decreased p-Akt in hepatic tissue. On the other hand, physical exercise was able to increase the performance of the mice and attenuate PCB levels and hyperglycemia in DIO + EXE mice. The above findings show that physical exercise seems to be able to regulate hyperglycemia in obese mice, suggesting the participation of PCB, which was enhanced in the obese condition and attenuated after a treadmill running protocol. This is the first study to be aimed at the role of exercise training in hepatic PCB levels, which may be a novel mechanism that can collaborate to reduce the development of hyperglycemia and type 2 diabetes in DIO mice.

In outbred mice, susceptibility or resistance to diet-induced obesity is associated with rapid changes in hypothalamic proopiomelanocortin (POMC) levels. Here, we evaluated 3 hypotheses that potentially explain the development of the different obesity phenotypes in outbred Swiss mice. First, rapid and differential changes in the gut microbiota in obesity-prone (OP) and obesity-resistant (OR) mice fed on a high-fat diet (HFD) might cause differential efficiencies in fatty acid harvesting leading to changes in systemic fatty acid concentrations that in turn affect POMC expression and processing. Second, independently of the gut microbiota, OP mice might have increased blood fatty acid levels after the introduction of a HFD, which could affect POMC expression and processing. Third, fatty acids might act directly in the hypothalamus to differentially regulate POMC expression and/or processing in OP and OR mice. We evaluated OP and OR male Swiss mice using 16S rRNA sequencing for the determination of gut microbiota; gas chromatography for blood lipid determination; and immunoblot and real-time polymerase chain reaction for protein and transcript determination and indirect calorimetry. Some experiments were performed with human pluripotent stem cells differentiated into hypothalamic neurons. We did not find evidence supporting the first 2 hypotheses. However, we found that in OP but not in OR mice, palmitate induces a rapid increase in hypothalamic POMC, which is followed by increased expression of proprotein convertase subtilisin/kexin type 1 PC1/3. Lentiviral inhibition of hypothalamic PC1/3 increased caloric intake and body mass in both OP and OR mice. In human stem cell-derived hypothalamic cells, we found that palmitate potently suppressed the production of POMC-derived peptides. Palmitate directly regulates PC1/3 in OP mice and likely has a functional impact on POMC processing.

O presente projeto visa mapear a distribuicao do receptor de acidos graxos omega 3 (?3), o GPR120, atraves da tecnica de imunofluorescencia. A localizacao do receptor nos diversos tecidos orgânicos podera predizer os possiveis locais de atuacao do ?3, em situacoes fisiologicas ou nao. Na obesidade, o processo inflamatorio prejudica a funcao de tecidos especificos. Caso haja o receptor no tecido a ser investigado, seja ativado pelo ?3, tal estrategia podera contribuir para o restabelecimento das funcoes teciduais.

Summary: Obesity has been associated with cognitive decline, atrophy of brain regions related to learning and memory, and higher risk of developing dementia. However, the molecular mechanisms underlying these neurological alterations are still largely unknown. Here, we investigate the effects of palmitate, a saturated fatty acid present at high amounts in fat-rich diets, in the brain. Palmitate is increased in the cerebrospinal fluid (CSF) of overweight and obese patients with amnestic mild cognitive impairment. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Palmitate induces astroglial and microglial activation in the mouse hippocampus, and its deleterious impact is mediated by microglia-derived tumor necrosis factor alpha (TNF-α) signaling. Our results establish that obesity is associated with increases in CSF palmitate. By defining a pro-inflammatory mechanism by which abnormal levels of palmitate in the brain impair memory, the results further suggest that anti-inflammatory strategies may attenuate memory impairment in obesity. : Obesity has been associated with cognitive decline. Melo et al. show that palmitate levels are increased in the CSF of overweight and obese humans. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Microglial-derived TNF-α mediates the deleterious actions of palmitate in the brain. Keywords: palmitate, memory impairment, obesity, brain inflammation, microglia, TNF-α, insulin signaling

Adiponectin is an adipokine that acts in the control of energy homeostasis. The adaptor protein containing the pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1) is a key protein in the adiponectin signaling. The APPL1 mediates a positive effect on the insulin signaling through the interaction with the phosphoinositide 3-kinase (PI3K). Thus, the present study aimed to explore the effects of an acute physical exercise session on the hypothalamic adiponectin signaling. Firstly, using bioinformatics analysis, we found a negative correlation between hypothalamic APPL1 mRNA levels and food consumption in several strains of genetically diverse BXD mice. Also, the mice and the human database revealed a positive correlation between the levels of APPL1 mRNA and PI3K mRNA. At the molecular level, the exercised mice showed increased APPL1 and PI3K (p110) protein contents in the hypothalamus of Swiss mice. Furthermore, the exercise increases co-localization between APPL1 and PI3K p110 predominantly in neurons of the arcuate nucleus of hypothalamus (ARC). Finally, we found an acute exercise session reduced the food intake 5 hr after the end of fasting. In conclusion, our results indicate that physical exercise reduces the food intake and increases some proteins related to adiponectin pathway in the hypothalamus of lean mice.

The consumption of saturated fatty acids is one of the leading risk factors for Alzheimer’s Disease (AD) development. Indeed, the short-term consumption of a high-fat diet (HFD) is related to increased inflammatory signals in the hippocampus; however, the potential molecular mechanisms linking it to AD pathogenesis are not fully elucidated. In our study, we investigated the effects of short-term HFD feeding (within 3, 7 and 10 days) in AD markers and neuroinflammation in the hippocampus of mice. The short period of HFD increased fasting glucose and HOMA-IR. Also, mice fed HFD increased the protein content of β-Amyloid, pTau, TNFα, IL1β, pJNK, PTP1B, peIF2α, CHOP, Caspase3, Cleaved-Caspase3 and Alzheimer-related genes (Bax, PS1, PEN2, Aph1b). At 10 days, both neuronal (N2a) and microglial (BV2) cells presented higher expression of inflammatory and apoptotic genes when stimulated with palmitate. These findings suggest that a short period of consumption of a diet rich in saturated fat is associated with activation of inflammatory, ER stress and apoptotic signals in the hippocampus of young mice.

Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants, Dietary fibers and SCFAs can exert a protective effect against respiratory syncytial virus (RSV). Here, the authors report that microbiota-derived acetate protects mice against RSV infection via GPR43- mediated type 1 interferon response induction in the lungs.

Low body weight gain and food intake are related to exhaustive training and overtraining; however, the molecular mechanisms responsible for these alterations remain unknown. The main aim of this study was to evaluate the effects of running overtraining (OT) protocols performed downhill, uphill and without inclination on the inflammatory pathway in the mouse hypothalamus. The rodents were randomized into the control (C), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR) groups. The body weights and food intake were recorded daily. The incremental load, exhaustive, rotarod and grip force tests were used to measure performance. At 36 h after the grip force test was performed at the end of OT protocols (i.e., week eight) and/or after a 2-week total recovery period (i.e., week 10), the hypothalamus and gastrocnemius were extracted for immunoblotting analysis. In addition, the serum was used to determine cytokine and leptin concentrations. From week 0 to week 8, the OTR/down group exhibited decreased body weight and food intake, and the OTR/up group increased their food intake. At week 10, the OTR/down group exhibited increased body weight, while the OTR group decreased their food intake. The OTR/down group exhibited increased IL-1beta, IL-6, TNF-alpha, pSAPK/JNK and SOCS3 levels at week eight. The OTR/down, OTR/up and OTR groups exhibited increased IL-10 levels at week 10. The OTR/up group displayed increased pJAK2 levels at week eight. While the OTR/down group exhibited increased IL-1beta levels, the OTR/down and OTR/up groups exhibited increased IL-6 and TNF-alpha levels, but decreased IL-10 levels in the gastrocnemius at week eight. The three OT protocols increased the IL-1beta and IL-6 levels, but only the OTR/down and OTR/up groups had increased TNF-alpha levels in serum at week eight. The serum leptin levels were lower for the OTR group compared with the CT group at week eight. In conclusion, the OTR/down protocol induced transitory hypothalamic inflammation with concomitant reductions in the body weight and food intake. After the 2-week total recovery period, the OTR/down group had reversed the hypothalamic inflammation, with the concomitant normalization of the body weight and food intake.

GPR120 and GPR40 were recently reported as omega-3 (ω3) receptors with anti-inflammatory properties. Physical exercise could increase the expression of these receptors in the liver, improving hepatic metabolism in obesity and type 2 diabetes. Our aim was to investigate GPR120/40 in the liver of lean and obese mice after acute or chronic physical exercise, with or without the supplementation of ω3 rich flaxseed oil (FS), as well as assess the impact of exercise and FS on insulin signaling and inflammation. Mice were fed a high-fat diet (HF) for 4 weeks to induce obesity and subsequently subjected to exercise with or without FS, or FS alone. Insulin signaling, inflammatory markers and GPR120/40 and related cascades were measured. Chronic, but not acute, exercise and FS increased GPR120, but not GPR40, activating β-arrestin-2 and decreasing the inflammatory response, as well as reducing fat depots in liver and adipose tissue. Exercise or a source of ω3 led to a higher tolerance to fatigue and an increased running distance and speed. The combination of physical exercise and ω3 food sources could provide a new strategy against obesity through the modulation of hepatic GPR120 and an increase in exercise performance.