The Taurine-Conjugated Bile Acid (TUDCA) Normalizes Insulin Secretion in Pancreatic ß-Cells Exposed to Fatty Acids: The Role of Mitochondrial Metabolism.

Bile acid tauroursodeoxycholic (TUDCA), formed from the association of ursodeoxycholic acid (UDCA) with taurine, has already been shown to increase mitochondrial biogenesis and cell survival, in addition to reduce reticulum stress markers in different cell types. However, its mechanism of action upon insulin secretion control in obesity is still unknown. In this sense, we seek to clarify whether taurine, associated with bile acid, could improve the function of the pancreatic ß-cells exposed to fatty acids through the regulation of mitochondrial metabolism. To test this idea, insulin-producing cells (INS1-E) were exposed to a fatty acid mix containing 500 µM of each palmitate and oleate for 48 hours treated or not with 300 µM of TUDCA. After that, glucose-stimulated insulin secretion and markers of mitochondrial metabolism were evaluated. Our results showed that the fatty acid mix was efficient in inducing hyperfunction of INS1-E cells as observed by the increase in insulin secretion, protein expression of citrate synthase, and mitochondrial density, without altering cell viability. The treatment with TUDCA normalized insulin secretion, reducing the protein expression of citrate synthase, mitochondrial mass, and the mitochondrial membrane potential. This effect was associated with a decrease in the generation of mitochondrial superoxide and c-Jun N-terminal kinase (JNK) protein content. The findings are also consistent with the hypothesis that TUDCA normalizes insulin secretion by improving mitochondrial metabolism and redox balance. Thus, it highlights likely mechanisms of the action of this bile acid on the glycemic homeostasis reestablishment in obesity.

Amino acid restriction alters survival mechanisms in pancreatic beta cells: possible role of the PI3K/Akt pathway.

BACKGROUND AND AIMS: Malnutrition in the early stages of life may lead to changes in the glycemic metabolism during adulthood, such as pancreatic beta cells dysfunction and failure. Therefore, this study aimed to evaluate the effects of an in vitro amino acid restriction model on the function and viability of pancreatic beta cells. METHODS: Insulin-producing cells (INS-1E) were maintained in control or amino acid restricted culture medium containing 1 × or 0.25 × of amino acids, respectively, for 48 h. RESULTS: Amino acid restricted group showed lower insulin secretion and insulin gene expression, reduced mitochondrial oxygen consumption rate and reactive oxygen species production. Besides, amino acid restricted group also showed higher levels of endoplasmic reticulum stress and apoptosis markers and enhanced Akt phosphorylation. However, even with higher levels of apoptosis markers, amino acid restricted group did not show higher levels of cell death unless the PI3K/Akt pathway was inhibited. CONCLUSION: Amino acid restricted beta cell viability seems to be dependent on the PI3K/Akt pathway.

Paternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germline.

BACKGROUND/AIMS: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease's (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. METHODS: We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. RESULTS: Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. CONCLUSION: Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.

The benefits of physical exercise for the health of the pancreatic ß-cell: a review of the evidence.

NEW FINDINGS: What is the topic of this review? This review discusses the evidence of the benefits of exercise training for ß-cell health through improvements in function, proliferation and survival which may have implications in the treatment of diabetes. What advances does it highlight? This review highlights how exercise may modulate ß-cell health in the context of diabetes and highlights the need for further exploration of whether ß-cell preserving effects of exercise translates to T1D. ABSTRACT: Physical exercise is a core therapy for type 1 and type 2 diabetes. Whilst the benefits of exercise for different physiological systems are recognised, the effect of exercise specifically on the pancreatic ß-cell is not well described. Here we review the effects of physical exercise on ß-cell health. We show that exercise improves ß-cell mass and function. The improved function manifests primarily through the increased insulin content of the ß-cell and its increased ability to secrete insulin in response to a glucose stimulus. We review the evidence relating to glucose sensing, insulin signalling, ß-cell proliferation and ß-cell apoptosis in humans and animal models with acute exercise and following exercise training programmes. Some of the mechanisms through which these benefits manifest are discussed.

Amino acid restriction increases ß-cell death under challenging conditions.

Malnutrition programs metabolism, favor dysfunction of ß cells. We aimed to establish an in vitro protocol of malnutrition, assessing the effect of amino acid restriction upon the ß cells. Insulin-producing cells INS-1E and pancreatic islets were maintained in RPMI 1640 medium containing 1× (Ctl) or 0.25× (AaR) of amino acids. We evaluated several markers of ß-cell function and viability. AaR Insulin secretion was reduced, whereas cell viability was unaltered. Calcium oscillations in response to glucose increased in AaR. AaR showed lower Ins1 RNAm, snap 25, and PKC (protein kinase C) protein content, whereas phospho-eIF2α was increased. AaR cells exposed to nutrient or chemical challenges displayed higher apoptosis rates. We showed that amino acid restriction programmed ß cell and induced functional changes. This model might be useful for the study of molecular mechanisms involved with ß-cell programming helping to establish novel therapeutic targets to prevent harmful outcomes of malnutrition.

Protein malnutrition mitigates the effects of a high-fat diet on glucose homeostasis in mice.

Nutrient malnutrition, during the early stages of development, may facilitate the onset of metabolic diseases later in life. However, the consequences of nutritional insults, such as a high-fat diet (HFD) after protein restriction, are still controversial. We assessed overall glucose homeostasis and molecular markers of mitochondrial function in the gastrocnemius muscle of protein-restricted mice fed an HFD until early adulthood. Male C57BL/6 mice were fed a control (14% protein-control diet) or a protein-restricted (6% protein-restricted diet) diet for 6 weeks. Afterward, mice received an HFD or not for 8 weeks (mice fed a control diet and HFD [CH] and mice fed a protein-restricted diet and HFD [RH]). RH mice showed lower weight gain and fat accumulation and did not show an increase in fasting plasma glucose and insulin levels compared with CH mice. RH mice showed higher energy expenditure, increased citrate synthase, peroxisome-proliferator-activated receptor gamma coactivator 1-alpha protein content, and higher levels of malate and α-ketoglutarate compared with CH mice. Moreover, RH mice showed increased AMPc-dependent kinase and acetyl coenzyme-A (CoA) carboxylase phosphorylation, lower intramuscular triacylglycerol content, and similar malonyl-CoA levels. In conclusion, protein undernourishment after weaning does not potentiate fat accumulation and insulin resistance in adult young mice fed an HFD. This outcome seems to be associated with increased skeletal muscle mitochondrial oxidative capacity and reduced lipids accumulation.

Exercise training protects human and rodent ß cells against endoplasmic reticulum stress and apoptosis.

Prolonged exercise has positive metabolic effects in obese or diabetic individuals. These effects are usually ascribed to improvements in insulin sensitivity. We evaluated whether exercise also generates circulating signals that protect human and rodent ß cells against endoplasmic reticulum (ER) stress and apoptosis. For this purpose, we obtained serum from humans or mice before and after an 8 wk training period. Exposure of human islets or mouse or rat ß cells to human or rodent sera, respectively, obtained from trained individuals reduced cytokine (IL-1ß+IFN-γ)- or chemical ER stressor-induced ß-cell ER stress and apoptosis, at least in part via activation of the transcription factor STAT3. These findings indicate that exercise training improves human and rodent ß-cell survival under diabetogenic conditions and support lifestyle interventions as a protective approach for both type 1 and 2 diabetes.-Paula, F. M. M., Leite, N. C., Borck, P. C., Freitas-Dias, R., Cnop, M., Chacon-Mikahil, M. P. T., Cavaglieri, C. R., Marchetti, P., Boschero, A. C., Zoppi, C. C., Eizirik, D. L. Exercise training protects human and rodent ß cells against endoplasmic reticulum stress and apoptosis.

Reduced glucose-induced insulin secretion in low-protein-fed rats is associated with altered pancreatic islets redox status.

In the present study, we investigated the relationship between early life protein malnutrition-induced redox imbalance, and reduced glucose-stimulated insulin secretion. After weaning, male Wistar rats were submitted to a normal-protein-diet (17%-protein, NP) or to a low-protein-diet (6%-protein, LP) for 60 days. Pancreatic islets were isolated and hydrogen peroxide (H2 O2 ), oxidized (GSSG) and reduced (GSH) glutathione content, CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and catalase (CAT) gene expression, as well as enzymatic antioxidant activities were quantified. Islets that were pre-incubated with H2 O2 and/or N-acetylcysteine, were subsequently incubated with glucose for insulin secretion measurement. Protein malnutrition increased CAT mRNA content by 100%. LP group SOD1 and CAT activities were 50% increased and reduced, respectively. H2 O2 production was more than 50% increased whereas GSH/GSSG ratio was near 60% lower in LP group. Insulin secretion was, in most conditions, approximately 50% lower in LP rat islets. When islets were pre-incubated with H2 O2 (100 µM), and incubated with glucose (33 mM), LP rats showed significant decrease of insulin secretion. This effect was attenuated when LP islets were exposed to N-acetylcysteine.

Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion.

Taurine (Tau) restores ß-cell function in obesity; however, its action is lost in malnourished obese rodents. Here, we investigated the mechanisms involved in the lack of effects of Tau in this model. C57BL/6 mice were fed a control diet (CD) (14% protein) or a protein-restricted diet (RD) (6% protein) for 6 wk. Afterward, mice received a high-fat diet (HFD) for 8 wk [CD + HFD (CH) and RD + HFD (RH)] with or without 5% Tau supplementation after weaning on their drinking water [CH + Tau (CHT) and RH + Tau (RHT)]. The HFD increased insulin secretion through mitochondrial metabolism in CH and RH. Tau prevented all those alterations in CHT only. The expression of the taurine transporter (Tau-T), as well as Tau content in pancreatic islets, was increased in CH but had no effect on RH. Protein malnutrition programs ß cells and impairs Tau-induced restoration of mitochondrial metabolism and biogenesis. This may be associated with modulation of the expression of Tau-T in pancreatic islets, which may be responsible for the absence of effect of Tau in protein-malnourished obese mice.-Branco, R. C. S., Camargo, R. L., Batista, T. M., Vettorazzi, J. F., Borck, P. C., dos Santos-Silva, J. C. R., Boschero, A. C., Zoppi, C. C., Carneiro, E. M. Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion.

Exercise increases pancreatic ß-cell viability in a model of type 1 diabetes through IL-6 signaling.

Type 1 diabetes (T1D) is provoked by an autoimmune assault against pancreatic ß cells. Exercise training enhances ß-cell mass in T1D. Here, we investigated how exercise signals ß cells in T1D condition. For this, we used several approaches. Wild-type and IL-6 knockout (KO) C57BL/6 mice were exercised. Afterward, islets from control and trained mice were exposed to inflammatory cytokines (IL-1ß plus IFN-γ). Islets from control mice and ß-cell lines (INS-1E and MIN6) were incubated with serum from control or trained mice or medium obtained from 5-aminoimidazole-4 carboxamide1-ß-d-ribofuranoside (AICAR)-treated C2C12 skeletal muscle cells. Subsequently, islets and ß cells were exposed to IL-1ß plus IFN-γ. Proteins were assessed by immunoblotting, apoptosis was determined by DNA-binding dye propidium iodide fluorescence, and NO(•) was estimated by nitrite. Exercise reduced 25, 75, and 50% of the IL-1ß plus IFN-γ-induced iNOS, nitrite, and cleaved caspase-3 content, respectively, in pancreatic islets. Serum from trained mice and medium from AICAR-treated C2C12 cells reduced ß-cell death, induced by IL-1ß plus IFN-γ treatment, in 15 and 38%, respectively. This effect was lost in samples treated with IL-6 inhibitor or with serum from exercised IL-6 KO mice. In conclusion, muscle contraction signals ß-cell survival in T1D through IL-6.

Leucine supplementation does not affect protein turnover and impairs the beneficial effects of endurance training on glucose homeostasis in healthy mice.

Endurance exercise training as well as leucine supplementation modulates glucose homeostasis and protein turnover in mammals. Here, we analyze whether leucine supplementation alters the effects of endurance exercise on these parameters in healthy mice. Mice were distributed into sedentary (C) and exercise (T) groups. The exercise group performed a 12-week swimming protocol. Half of the C and T mice, designated as the CL and TL groups, were supplemented with leucine (1.5 % dissolved in the drinking water) throughout the experiment. As well known, endurance exercise training reduced body weight and the retroperitoneal fat pad, increased soleus mass, increased VO2max, decreased muscle proteolysis, and ameliorated peripheral insulin sensitivity. Leucine supplementation had no effect on any of these parameters and worsened glucose tolerance in both CL and TL mice. In the soleus muscle of the T group, AS-160(Thr-642) (AKT substrate of 160 kDa) and AMPK(Thr-172) (AMP-Activated Protein Kinase) phosphorylation was increased by exercise in both basal and insulin-stimulated conditions, but it was reduced in TL mice with insulin stimulation compared with the T group. Akt phosphorylation was not affected by exercise but was lower in the CL group compared with the other groups. Leucine supplementation increased mTOR phosphorylation at basal conditions, whereas exercise reduced it in the presence of insulin, despite no alterations in protein synthesis. In trained groups, the total FoxO3a protein content and the mRNA for the specific isoforms E2 and E3 ligases were reduced. In conclusion, leucine supplementation did not potentiate the effects of endurance training on protein turnover, and it also reduced its positive effects on glucose homeostasis.

Recreational Anabolic-Androgenic Steroid Use Associated With Liver Injuries Among Brazilian Young Men.

BACKGROUND: The recreational use of anabolic-androgenic steroids (AAS) has reached alarming levels among healthy people. However, several complications have been related to consumption of these drugs, including liver disorders. OBJECTIVE: To evaluate the prevalence of liver injuries in young Brazilian recreational AAS users. METHODS: Between February/2007 and May/2012 asymptomatic bodybuilders who were ≥18 years old and reported AAS use for ≥6 months were enrolled. All had clinical evaluations, abdominal ultrasound (AUS), and blood tests. RESULTS: 182 individuals were included in the study. The median age (interquartile range) was 26.0 years (22.0-30.0) and all were male. Elevated liver enzyme levels were observed in 38.5% (n = 70) of AAS users, and creatine phosphokinase was normal in 27.1% (n = 19) of them. Hepatic steatosis was observed by AUS in 12.1% of the sample. One individual had focal nodular hyperplasia and another had hepatocellular adenoma. One case each of hepatitis B and C virus infection was found. A diagnosis of toxic liver injury was suggested in 23 (12.6%) AAS users without a history of alcohol or other medications/drugs consumption, or evidence of other liver diseases. CONCLUSIONS/IMPORTANCE: Young Brazilian recreational AAS users presented a wide spectrum of liver injuries that included hepatotoxicity, fatty liver, and liver neoplasm. They also presented risk factors for liver diseases such as alcohol consumption and hepatitis B and C virus infection. The results suggest that the risk of AAS use for the liver may be greater than the esthetic benefits, and demonstrate the importance of screening AAS users for liver injuries.

Hydrogen peroxide production regulates the mitochondrial function in insulin resistant muscle cells: effect of catalase overexpression.

The mitochondrial redox state plays a central role in the link between mitochondrial overloading and insulin resistance. However, the mechanism by which the ROS induce insulin resistance in skeletal muscle cells is not completely understood. We examined the association between mitochondrial function and H2O2 production in insulin resistant cells. Our hypothesis is that the low mitochondrial oxygen consumption leads to elevated ROS production by a mechanism associated with reduced PGC1α transcription and low content of phosphorylated CREB. The cells were transfected with either the encoded sequence for catalase overexpression or the specific siRNA for catalase inhibition. After transfection, myotubes were incubated with palmitic acid (500µM) and the insulin response, as well as mitochondrial function and fatty acid metabolism, was determined. The low mitochondrial oxygen consumption led to elevated ROS production by a mechanism associated with ß-oxidation of fatty acids. Rotenone was observed to reduce the ratio of ROS production. The elevated H2O2 production markedly decreased the PGC1α transcription, an effect that was accompanied by a reduced phosphorylation of Akt and CREB. The catalase transfection prevented the reduction in the phosphorylated level of Akt and upregulated the levels of phosphorylated CREB. The mitochondrial function was elevated and H2O2 production reduced, thus increasing the insulin sensitivity. The catalase overexpression improved mitochondrial respiration protecting the cells from fatty acid-induced, insulin resistance. This effect indicates that control of hydrogen peroxide production regulates the mitochondrial respiration preventing the insulin resistance in skeletal muscle cells by a mechanism associated with CREB phosphorylation and ß-oxidation of fatty acids.

Taurine-induced insulin signalling improvement of obese malnourished mice is associated with redox balance and protein phosphatases activity modulation.

BACKGROUND & AIMS: Obese protein malnourished mice display liver insulin resistance and taurine (TAU) seems to attenuate this effect. The association between early-life malnutrition and hepatic redox balance in diet-induced insulin resistance is unknown. We investigated TAU supplementation effects upon liver redox state and insulin signalling in obese protein malnourished mice. METHODS: Weaned male C57BL-6 mice were fed a control (14% protein - C) or a protein-restricted diet (6% protein - R) for 6 weeks. Afterwards, mice received a high-fat diet (34% fat - HFD) for 8 weeks (CH - RH). Half of the HFD-mice were supplemented with TAU (5%) throughout the treatment (CHT - RHT). Body and tissues' weight, respiratory quotient (RQ), glucose tolerance and insulin sensitivity, hepatic oxidant and antioxidant markers and insulin cascade proteins were assessed. RESULTS: Protein restriction leads to typical features whereas HFD was able to induce a catch-up growth in RH. HFD-groups showed higher energy intake and adiposity, lower energy expenditure and altered RQ. Glucose tolerance and insulin sensitivity were impaired in HFD-groups and TAU attenuated these effects. H2 O2 content was increased in CHT and RHT despite no differences in antioxidant enzymes and GSH concentration. AKT and PTEN phosphorylation were significantly increased in CHT but not in RHT. CONCLUSION: Our data provide evidence for an association between TAU-induced improved glycaemic control because of PTEN inactivation and higher AKT phosphorylation. These effects seem to be related with altered hepatic redox balance in obese mice, and this effect is impaired by protein malnutrition.

The influence of concomitant use of alcohol, tobacco, cocaine, and anabolic steroids on lipid profiles of Brazilian recreational bodybuilders.

Anabolic-androgenic steroids (AAS) are used to enhance physical performance and/or appearance. The aim of this study was to evaluate the influence of the concomitant use of alcohol, tobacco, cocaine, and AAS on blood lipid profiles of 145 asymptomatic male bodybuilders from the Northeast region of Brazil. Interviews, clinical exams, and serological evaluations were performed on all participants between 2007 and 2009. All subjects' self-reported use of testosterone or its derivatives, 118 individuals reported alcohol intake, 27-reported cigarette smoking, and 33 confirmed cocaine use. Four subjects were users of all drugs at the same time. Higher levels of total cholesterol and LDL-cholesterol were observed among concomitant users of alcohol, tobacco, cocaine, and AAS. The study's limitations are noted.

Resistance training maintains physical function but does not prevent changes in body composition and biochemical markers after detraining in aging adults.

OBJECTIVE: The objective of the present study was to analyze the effects of 10 weeks of resistance training (RT) and subsequent 4 weeks of detraining on physical function, body composition, and biochemical markers in aging adults. METHODS: The study sample was selected by convenience and consisted of 12 women with a mean age of 58 ± 7 years. Physical function [Latin-American Group of Development for Maturity (GDLAM) general index], body composition, total and fractional cholesterol, triglycerides, and glycemia were assessed before and after RT (10 weeks) and detraining (4 weeks). RESULTS: After 10 weeks of RT, there were improvements in fat-free mass (39.1 ± 4.2 vs. 39.9 ± 4.4 kg; p < 0.05 and d = 0.2), fat mass (39.9 ± 6.3% vs. 38.7 ± 6.4%; p < 0.05 and d = -0.2), conicity index (1.47 ± 0.07 vs. 1.43 ± 0.06; p = 0.001 and d = -0.6), and physical function (GDLAM index [27.2 ± 5.5 vs. 25.0 ± 4.7; p = 0.001 and d = -0.4]). Significant improvements were also found in total cholesterol (271.8 ± 75.7 vs. 217.2 ± 52.2 mg/dL; p < 0.01 and d = -0.8), LDL-cholesterol (196.5 ± 61.6 vs. 159.3 ± 38.5 mg/dL; p < 0.01 and d = -0.7), HDL-cholesterol (53.1 ± 7.3 vs. 64.3 ± 23.7 mg/dL; p < 0.05 and d = 0.7), and triglycerides (165.8 ± 32.6 vs. 139.9 ± 46.6 mg/dL; p = 0.001 and d = -0.6). After the detraining period, all benefits in physical function were successfully maintained. CONCLUSION: RT provided benefits in physical function, body composition, and biochemical markers in aging adults. However, 4-week detraining impaired body composition and biochemical markers in the investigated sample.

Inflammation of the hypothalamus leads to defective pancreatic islet function.

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic ß-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic ß-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.

Tauroursodeoxycholic acid improves glucose tolerance and reduces adiposity in normal protein and malnourished mice fed a high-fat diet.

Early childhood malnutrition may facilitate the onset of obesity and diabetes mellitus in adulthood which, when established, makes it more resistant to therapeutic interventions. The beneficial effects of tauroursodeoxycholic acid (TUDCA) in glucose homeostasis and body fat accumulation were analyzed in protein-restricted mice fed a high-fat diet (HFD). C57BL/6 mice were fed a control (14% protein [C]) or a protein-restricted (6% protein [R]) diet for 6 weeks. Afterward, mice received an HFD or not for 12 weeks (C mice fed an HFD [CH] and R mice fed an HFD [RH]). In the last 15 days of this period, half of the mice fed a HFD received i.p. PBS (groups CH and RH) or 300 mg/kg TUDCA (groups CHT and RHT). RH mice developed obesity, as demonstrated by the increase in fat accumulation, liver steatosis, and metabolic inflexibility. Additionally, showed glucose intolerance and insulin hypersecretion. TUDCA reduced adiposity and improve metabolic flexibility through increased HSL phosphorylation and CPT1 expression in eWAT and BAT, and reduced ectopic fat deposition by activating the AMPK/HSL pathway in the liver. Also, improved glucose tolerance and insulin sensitivity, normalizing insulin secretion by reducing GDH expression and increasing insulin peripheral sensitivity by greater expression of the IRß in muscle and adipose tissue and reducing PEPCK liver expression. Our data indicate that TUDCA reduces global adiposity and improves glucose tolerance and insulin sensitivity in protein malnourished mice fed a HFD. Therefore, this is a possible strategy to reverse metabolic disorders in individuals with the double burden of malnutrition.