Ageing leads to changes in body composition, including increased adiposity and reduced skeletal muscle mass and force. The alterations in ageing skeletal muscle result from impaired proteostasis driven by factors such as chronic inflammation, hormonal changes and reduced nutrient absorption. Those age-related changes in body composition and skeletal muscle compromise mobility and increase the risk of falls, fractures and metabolic disorders. Tauroursodeoxycholic acid (TUDCA), a bile acid with known benefits in chronic diseases, has been shown by our group to improve cognition and metabolic homeostasis in ageing and Alzheimer's disease mouse models. Interestingly, in previous studies, TUDCA treatment was also associated with increased skeletal muscle mass in ageing mice, leading us to hypothesize that TUDCA could target skeletal muscle to reduce age-related muscle loss. To explore this, we treated 18-month-old C57BL/6 mice with TUDCA or vehicle for 20 days, using 3-month-old mice as a young control group. We demonstrate that TUDCA treatment decreases body weight while increasing skeletal muscle mass, restores muscle fibre size and preserves functional integrity. Additionally, TUDCA enhances skeletal muscle insulin sensitivity through increased AKT activation and reduces tissue inflammation. Such improvements collectively support the restoration of skeletal muscle proteostasis, as indicated by increased protein synthesis and phosphorylation of key anabolic signalling pathways, including ribosomal protein S6 kinase beta-1 (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These findings contribute to a better understanding of TUDCA's actions on skeletal muscles of ageing mice and highlight its role as a promising strategy against age-related muscle loss. KEY POINTS: Tauroursodeoxycholic acid (TUDCA) treatment attenuates skeletal muscle loss in ageing mice. TUDCA improves skeletal muscle insulin sensitivity and restores AKT signalling. TUDCA exerts an anti-inflammatory effect in skeletal muscle of ageing mice. TUDCA emerges as a potential therapy for age-related skeletal muscle loss.

ABSTRACT Background Early-life protein restriction is a risk factor for cardiovascular disease, yet the mechanisms underlying vascular dysfunction and therapeutic strategies remain poorly defined. Tauroursodeoxycholic acid (TUDCA) is a bile acid that inhibits endoplasmic reticulum (ER) stress and has therapeutic potential in metabolic diseases. We hypothesized that TUDCA exerts vasculoprotective effects in the setting of post-weaning protein restriction. Methods Post-weaning male and female mice fed a normoprotein (14% protein) or protein-restricted (6% protein, isocaloric) diet for 105 days. In the last 15 days, mice received TUDCA (300 mg/kg/day) or vehicle. Vascular function was assessed in the thoracic aorta with or without perivascular adipose tissue (PVAT). mRNA expression and histological analyses were performed in aorta and PVAT. Results Long-term protein restriction resulted in endothelial dysfunction, vascular hypocontractility, and loss of the anticontractile effect of PVAT in males, but not females. These alterations were restored by TUDCA. In aorta, TUDCA normalized expression of eNOS and contractile phenotype-related genes α-actin, SM22α, Cav1.2 whereas, in the PVAT, TUDCA restored lipid content and expression of PRDM16, PPARγ, PGC1α, leptin, and OB-Rb in protein-restricted mice. TUDCA attenuated fibrosis and ER stress markers while increased the bile acid receptor FXR expression in both tissues. Similar to TUDCA, ER stress inhibition with 4-phenylbutyric acid restored vascular and PVAT function in protein-restricted male mice. Conclusions Post-weaning protein restriction induces vascular and PVAT dysfunction and fibrosis in males, associated with ER stress. TUDCA significantly attenuates these alterations, supporting its potential as a therapeutic strategy for vascular complications associated with early-life undernutrition.

Introduction and Objective: Mice subjected to a protein-restricted diet during the post-weaning period exhibit a morphological reduction in pancreatic β cell mass and impaired insulin secretion. The insufficient mass of functional β cells and the imbalance in the proportion of α cells contribute to the progression of diabetes. To restore the β cell mass is crucial to protect against diabetes development. The TUDCA treatment has restored the mass and number of β cells per islet in diabetes mice models. Here, we determined the effects of TUDCA on the morphology and function of the endocrine pancreas in mice subjected to post-weaning protein restriction. Methods: Male C57Bl/6J mice, 30 days old, were fed a 14% protein diet (group C) or a 6% protein diet (group R) for 16 weeks. During the last 2 weeks, 50% of the mice from each group received intraperitoneally daily doses of 300 mg/kg body weight of TUDCA (CT and RT), while the remaining mice received PBS (C and R). Data were analyzed using two-way ANOVA with significance at P≤ 0.05. Results: R mice exhibited a reduced glucose-stimulated insulin secretion, associated with a decreased β cell mass and an increased α cell mass. RT mice secreted more insulin and showed a greater absolute mass and a higher relative mass of β cells per pancreatic islet, while α cells were reduced. Furthermore, using IF, bi-hormonal Insulin+/Glucagon+ cells were identified, along with NKX6.1+/Glucagon+ cells and PDX1+/Glucagon+ cells in islets from RT mice, suggesting the presence of α cells with β cell identity. These results indicate that TUDCA may modulate the islet plasticity. Conclusion: We conclude that TUDCA modified the architecture of pancreatic islet cells and reduced parameters related to α cells, restoring insulin secretion in undernutrition mice, confirming that TUDCA may be crucial to restore the β cell mass and function in different dysfunctional β cell models protecting against diabetes onset. L.M. Barreto dos Santos: None. T. Araujo: None. S. Ferreira: None. M.C. Silva: None. E.M. Carneiro: None.

Introduction and Objective: Undernutrition remains a persistent nutritional problem in low-income countries, contributing to disease development, like metabolic dysfunction-associated fatty liver disease (MAFLD). However, the molecular mechanisms underlying the onset of MAFLD in undernutrition are not yet fully understood. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contacts in the onset and progression of MAFLD during undernutrition. Methods: 30-day-old male C57BL6J mice were fed for three months with a diet containing either 14% protein (Control - C) or 6% protein (Protein Restriction - R). Blood and liver samples were collected for functional and molecular analyses. Data were analyzed using Student's t-test or Mann-Whitney test, with statistical significance at P < 0.05. Results: R mice exhibited a 31% reduction in final body weight (P < 0.001) and a 20% decrease in total plasma protein levels (P < 0.05), validating the protein undernutrition model. Protein restriction led to increased hepatic triglyceride (51%, P < 0.05) and cholesterol (44%, P < 0.05) content, elevated alanine transaminase activity (12%, P < 0.05), and higher collagen deposition (28%, P < 0.05), indicative of MAFLD development. Hepatocytes from R mice exhibited greater ER-mitochondria contact (35%, P < 0.05) compared to C mice. This increase was associated with higher reactive oxygen species (ROS) levels (28%, P < 0.05) and reduced basal respiration and maximum mitochondrial capacity (35% and 46%, P < 0.05) in the liver from R mice. Conclusion: These findings demonstrated that protein restriction increases hepatocyte ER-mitochondria contact, enhancing ROS production, impairing mitochondrial metabolism, and contributing to lower fatty acid oxidation. Understanding these mechanisms may pave the way for targeted therapeutic strategies to mitigate MAFLD in undernourished individuals. T. Araujo: None. L.M. Barreto dos Santos: None. J.A. Junior: None. E.M. Carneiro: None. FAPESP (2023/02152-4)

Abstract Combined oral contraceptives (COC)s are the contraceptive method of choice for millions of women worldwide. In this study, we aimed to investigate the effects of COC administration, composed of 17α-ethinylestradiol (EE2) and drospirenone (DRSP), on obesity, glucose tolerance, and hepatic steatosis in female mice. Eighty-day-old Swiss female mice were fed either a standard diet (SD) or a high-fat diet (HFD) and daily received, via gavage, 0.2 mL of distilled water (CTL-SD and CTL-HFD groups) with or without COC (COC-SD and COC-HFD groups) for 65 days. COC administration attenuated body weight and adiposity gains and prevented glucose intolerance induced by HFD in COC-HFD females. These effects were accompanied by the upregulation of Prdm16 and Ucp-1 genes in the brown adipose tissue (BAT) of COC-HFD mice. These females also exhibited a lower hepatic steatosis score than CTL-HFD mice; however, their liver parenchyma showed an increased number of inflammatory foci, and up-regulation of the Il-1β gene. Thus, COC administration in female mice attenuated obesity development induced by HFD, possibly through modulation of BAT function, while the increased hepatic expression of the pro-inflammatory cytokine IL-1β suggests that COC exacerbated HFD-induced liver inflammation.

The epidemic of obesity has increased worldwide and is associated with comorbidities such as diabetes and cardiovascular disease. In this context, strategies that modulate body weight and improve glycemic metabolism have increased, and bariatric surgeries such as Sleeve Gastrectomy (SG) have been highlighted in obesity treatment. However, the mechanism by which SG reduces body weight and improves glycemic control remains unknown. Thus, in this study, we aimed to evaluate food intake and the expression of hypothalamic genes involved with the regulation of this process in diet-induced obese mice submitted to SG. For this, we used C57BL/6 mice submitted to a 10-week high-fat diet protocol and submitted to SG. Food intake, fed and fasted glycemia, as well as hypothalamic anorexigenic and orexigenic gene expression were evaluated 4 weeks after the surgical procedure. First, we observed that SG reduces body weight (44.19 ± 0.47 HFD, 43.51 ± 0.71 HFD-SHAM, and 38.22 ± 1.31 HFD-SG), fasting glycemia (115.0 ± 4.60 HFD, 122.4 ± 3.48 HFD-SHAM, and 93.43 ± 4.67 HFD-SG), insulinemia (1.77 ± 0.15 HFD, 1.92 ± 0.27 HFD-SHAM, and 0.93 ± 0.05 HFD-SG), and leptinemia (5.86 ± 1.38 HFD, 6.44 ± 1.51 HFD-SHAM, and 1.43 ± 0.35 HFD-SG) in obese mice. Additionally, SG reduces food (5.15 ± 0.18 HFD, 5.49 ± 0.32, HFD-SHAM, and 3.28 ± 0.26 HFD-SG) and total (16.88 ± 0.88 HFD, 17.05 ± 0.42, HFD-SHAM, and 14.30 ± 0.73 HFD-SG) calorie intake without alterations in anorexigenic and orexigenic gene expression. In conclusion, these data indicate that SG improves obesity-associated alterations at least in part by a reduction in food intake. This effect is not associated with the canonical food intake pathway in the hypothalamus, indicating the involvement of non-canonical pathways in this process.

Genetic factors, diet, lifestyle, and other factors lead to various complications in the body, such as obesity and other chronic diseases. The inflammatory state caused by excessive accumulation of body fat affects the pathways related to the control of glycemic homeostasis, leading to a high demand for insulin, to subsequent failure of stressed β cells, and development of type 2 diabetes mellitus (T2DM). The study of new endocrine signalers, such as bile acids (BAs), becomes necessary as it allows the development of alternatives for T2DM treatment. In this work, a methodology was developed to quantify tauroursodeoxycholic BA (TUDCA) in liver cells of the HepG2 strain treated in hyperlipidic medium. This BA helps to improve insulin clearance by increasing the expression of the insulin-degrading enzyme, restoring sensitivity to this hormone, and making it viable for treating T2DM. Herein, a targeted metabolomic method for TUDCA determination in extracellular medium of hepatocyte matrices by micellar electrokinetic chromatography-UV was optimized, validated, and applied. The optimized background electrolyte was composed of 40 mmol/L sodium cholate and 30 mmol/L sodium tetraborate at pH 9.0. The following figures of merit were evaluated: linearity, limit of quantification, limit of detection, accuracy, and precision. Data obtained with the validated electrophoretic method showed a self-stimulation of TUDCA production in media supplemented only with BA. On the other hand, TUDCA concentration was reduced in the hyperlipidic medium. This suggests that, in these media, the effect of TUDCA is reduced, such as self-stimulated production and consequent regulation of glycemic homeostasis. Therefore, the results reinforce the need for investigating TUDCA as a potential T2DM biomarker as well as its use to treat several comorbidities, such as obesity and diabetes mellitus.

Background: The thyroid gland is susceptible to abnormal epithelial cell growth, often resulting in thyroid dysfunction. The serine-threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, proliferation, and growth through two different protein complexes, mTORC1 and mTORC2. The PI3K-Akt-mTORC1 pathway's overactivity is well associated with heightened aggressiveness in thyroid cancer, but recent studies indicate the involvement of mTORC2 as well. Methods: To elucidate mTORC1's role in thyrocytes, we developed a novel mouse model with mTORC1 gain of function in thyrocytes by deleting tuberous sclerosis complex 2 (TSC2), an intracellular inhibitor of mTORC1. Results: The resulting TPO-TSC2(KO) mice exhibited a 70-80% reduction in TSC2 levels, leading to a sixfold increase in mTORC1 activity. Thyroid glands of both male and female TPO-TSC2(KO) mice displayed rapid enlargement and continued growth throughout life, with larger follicles and increased colloid and epithelium areas. We observed elevated thyrocyte proliferation as indicated by Ki67 staining and elevated cyclin D3 expression in the TPO-TSC2(KO) mice. mTORC1 activation resulted in a progressive downregulation of key genes involved in thyroid hormone biosynthesis, including thyroglobulin (Tg), thyroid peroxidase (Tpo), and sodium-iodide symporter (Nis), while Tff1, Pax8, and Mct8 mRNA levels remained unaffected. NIS protein expression was also diminished in TPO-TSC2(KO) mice. Treatment with the mTORC1 inhibitor rapamycin prevented thyroid mass expansion and restored the gene expression alterations in TPO-TSC2(KO) mice. Although total thyroxine (T4), total triiodothyronine (T3), and TSH plasma levels were normal at 2 months of age, a slight decrease in T4 and an increase in TSH levels were observed at 6 and 12 months of age while T3 remained similar in TPO-TSC2(KO) compared with littermate control mice. Conclusions: Our thyrocyte-specific mouse model reveals that mTORC1 activation inhibits thyroid hormone (TH) biosynthesis, suppresses thyrocyte gene expression, and promotes growth and proliferation.

Impaired insulin production and/or secretion by pancreatic beta cells can lead to high blood glucose levels and type 2 diabetes (T2D). Therefore, investigating new proteins involved in beta cell response to stress conditions could be useful in finding new targets for therapeutic approaches. KH-type splicing regulatory protein (KSRP) is a protein usually involved in gene expression due to its role in post-transcriptional regulation. Although there are studies describing the important role of KSRP in tissues closely related to glucose homeostasis, its effect on pancreatic beta cells has not been explored so far. Pancreatic islets from diet-induced obese mice (C57BL/6JUnib) were used to determine KSRP expression and we also performed in vitro experiments exposing INS-1E cells (pancreatic beta cell line) to different stressors (palmitate or cyclopiazonic acid—CPA) to induce cellular dysfunction. Here we show that KSRP expression is reduced in all the beta cell dysfunction models tested. In addition, when manipulated to knock down KSRP, beta cells exhibited increased death and impaired insulin secretion, whereas KSRP overexpression prevented cell death and increased insulin secretion. Taken together, our findings suggest that KSRP could be an important target to protect beta cells from impaired functioning and death.

The teaching of physiology plays a crucial role in the education of health care professionals. However, traditional approaches to physiology classes in undergraduate health courses in Brazil often result in passive student participation. Research has shown that active methodologies are more effective in the learning process. In this study, we introduce the game "Who Am I?-Cellular Signal Transduction Edition" as an educational tool. This game follows a popular format with well-known rules and aims to enhance understanding of basic concepts related to hormones, cell signaling, and the functioning of the endocrine system. Our findings demonstrate that the game improves student knowledge and fosters enthusiasm and active engagement among participants. Additionally, student feedback has indicated a high level of appreciation for the game. By incorporating active learning strategies and a gamified approach, "Who Am I?-Cellular Signal Transduction Edition" provides a practical and enjoyable way of teaching physiology. This innovative educational tool has the potential to revolutionize physiology instruction. Demonstrating significant improvement in students' understanding, the game underscores its efficacy in enhancing knowledge acquisition and comprehension of cellular signaling and endocrine physiology topics.NEW & NOTEWORTHY We developed "Who Am I?-Cellular Signal Transduction Edition" to assist students in comprehending concepts of cellular signal transduction. This simple and cost-effective tool is perfect for educational settings with limited resources, and it encourages active learning for both small and large groups. Pre- and posttests have shown that it effectively enhances knowledge of hormonal actions and cellular signaling. Positive feedback from students emphasizes its value in reinforcing understanding and improving classroom engagement, making it a promising educational tool.

TUDCA treatment restores early protein-restriction-induced aortic hipocontractility and endothelial dysfunction Israelle Netto Freitas1,2; Joel da Silva Junior2; Jamaira Aparecida Victorio1,2; Everardo Magalhães Carneiro1,2; Ana Paula Davel1 1Laboratory of Vascular Biology and 2Obesity and Comorbidities Center-OCRC, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP, Brazil. Malnutrition is a risk factor for the development of vascular dysfunction. Tauroursodeoxycholic acid (TUDCA) inhibits endoplasmic reticulum stress (ERS) and has been demonstrated to be protective against vascular dysfunction in cardiometabolic diseases. Therefore, we hypothesized that TUDCA could be beneficial for endothelial function and vascular contractility during malnutrition. For this, post-weaning male and female mice fed a normoprotein (NP, 14% protein) or low protein (LP, 6% protein, isocaloric) diet for 15 weeks. In the last 2 weeks, some NP and LP animals received TUDCA (300 mg/kg/day, ip) or vehicle. At the end of the treatment, body weight (BW) and systolic blood pressure (SBP) were evaluated and thoracic aortic isolated to assess vascular responses, fluorescence to dihydroethidium (DHE) and gene expression. As results, BW was reduced and SBP was elevated in male and female protein-restricted groups; TUDCA treatment restored SBP but not BW. Only in males, protein restriction impaired endothelium-dependent relaxation to acetylcholine and reduced contractility (phenylephrine, serotonin, and TXA2 analogue U46619) in aorta. TUDCA reversed both endothelial dysfunction and hypocontractility in LP male group. We found reduced expression of smooth muscle 22α (SM22α), α-actin and L-type calcium channel (Cav1.2) in aorta from male LP compared to NP, which was restored by TUDCA treatment. In addition, aorta from male LP group showed increased DHE fluorescence and gene expression of the ERS markers GRP78, ATF6, PERK, IRE1α and CHOP. These alterations were reversed by TUDCA. In conclusion, our data suggest that post-weaning protein restriction results in endothelial dysfunction and aortic hypocontractility in males only. These alterations were associated with oxidative stress and reduced expression of vascular contractile and ERS markers. TUDCA treatment rescued vascular contraction and endothelial function in early protein-restricted mice evidencing the therapeutic potential of this bile acid for the vascular complications associated with undernutrition. The authors have nothing to disclose. Funding source: São Paulo Research Foundation (FAPESP). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose–insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression.

Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases.

Healthy perivascular adipose tissue (PVAT) has anticontractile, anti-inflammatory and antioxidant actions that can be disrupted by cardiometabolic risk factors. In the present study we hypothesized that protein restriction in the early phases of development could result in PVAT dysfunction and tauroursodeoxycholic acid (TUDCA) could be beneficial by inhibiting endoplasmic reticulum stress (ERS). To test this hypothesis, post-weaning male and female mice fed a normoprotein (NP, 14% protein) or a low protein (LP, 6% protein, isocaloric) diet for 15 weeks. In the last 2 weeks, some NP and LP animals received TUDCA (300 mg/kg/day) or vehicle. At the end of treatment, thoracic aorta was isolated to assess vascular responses with or without adjacent PVAT, as well as PVAT gene expression and histology. As results, the presence of PVAT reduced the phenylephrine-induced contraction in aorta of female NP and LP and male NP but not in male LP, suggesting LP-induced PVAT dysfunction in males only. In males, aortic PVAT from LP group showed less lipid content and increased collagen deposition. Decreased expression of PRDM-16, PPAR-γ, PGC-1α and leptin was observed in PVAT of LP group. These functional and morphological PVAT alterations in males were reversed by TUDCA treatment. Because TUDCA inhibits ERS, next we evaluated gene expression of ERS markers. There was an increased expression of GRP78, ATF4/6, IRE1α, and CHOP in PVAT from LP group, which was normalized by TUDCA. Also, TUDCA treatment normalized the reduced PVAT expression of the TUDCA receptor FXR in LP group. In conclusion, our data suggest that post-weaning protein-restriction impairs PVAT function and structure in males. These changes were associated with decreased expression of adipogenesis and adipocyte differentiation factors, and increased ERS markers. TUDCA reversed protein-restriction-induced PVAT abnormalities. Therefore, TUDCA emerges as a potential therapy for vascular complications associated with early undernutrition. The authors have nothing to disclose. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Undernutrition is still a recurring nutritional problem in low and middle-income countries. It is directly associated with the social and economic sphere, but it can also negatively impact the health of the population. In this sense, it is believed that undernourished individuals may be more susceptible to the development of non-communicable diseases, such as diabetes mellitus, throughout life. This hypothesis was postulated and confirmed until today by several studies that demonstrate that experimental models submitted to protein undernutrition present alterations in glycemic homeostasis linked, in part, to the reduction of insulin secretion. Therefore, understanding the changes that lead to a reduction in the secretion of this hormone is essential to prevent the development of diabetes in undernourished individuals. This narrative review aims to describe the main molecular changes already characterized in pancreatic β cells that will contribute to the reduction of insulin secretion in protein undernutrition. So, it will provide new perspectives and targets for postulation and action of therapeutic strategies to improve glycemic homeostasis during this nutritional deficiency.

Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 ( Fgfr1) and its coreceptor β-klotho ( Klb), both in pancreatic islets from VSG mice and in INS-1E β-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

Interesterified fats have been used to replace trans-fat in ultra-processed foods. However, their metabolic effects are not completely understood. Hence, this study aimed to investigate the effects related to glucose homeostasis in response to interesterified palm oil or refined palm oil intake. Four-week-old male Swiss mice were randomly divided into four experimental groups and fed the following diets for 8 weeks: a normocaloric and normolipidic diet containing refined palm oil (PO group) or interesterified palm oil (IPO group); a hypercaloric and high-fat diet containing refined PO (POHF group) or interesterified PO (IPOHF group). Metabolic parameters related to body mass, adiposity and food consumption showed no significant differences. As for glucose homeostasis parameters, interesterified palm oil diets (IPO and IPOHF) resulted in higher glucose intolerance than unmodified palm oil diets (PO and POHF). Euglycemic-hyperinsulinemic clamp assessment showed a higher endogenous glucose production in the IPO group compared with the PO group. Moreover, the IPO group showed significantly lower p-AKT protein content (in the muscle and liver tissues) when compared with the PO group. Analysis of glucose-stimulated static insulin secretion (11.1 mmol/L glucose) in isolated pancreatic islets showed a higher insulin secretion in animals fed interesterified fat diets (IPO and IPOHF) than in those fed with palm oil (PO and POHF). Interesterified palm oil, including in normolipidic diets, can impair insulin signaling in peripheral tissues and increase insulin secretion by β-cells, characterizing insulin resistance in mice.

Adipose tissue is an organ with metabolic and endocrine activity. White, brown and ectopic adipose tissues have different structure, location, and function. Adipose tissue regulates energy homeostasis, providing energy in nutrient-deficient conditions and storing it in high-supply conditions. To attend to the high demand for energy storage during obesity, the adipose tissue undergoes morphological, functional and molecular changes. Endoplasmic reticulum (ER) stress has been evidenced as a molecular hallmark of metabolic disorders. In this sense, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), a bile acid conjugated to taurine with chemical chaperone activity, has emerged as a therapeutic strategy to minimize adipose tissue dysfunction and metabolic alterations associated with obesity. In this review, we highlight the effects of TUDCA and receptors TGR5 and FXR on adipose tissue in the setting of obesity. TUDCA has been demonstrated to limit metabolic disturbs associated to obesity by inhibiting ER stress, inflammation, and apoptosis in adipocytes. The beneficial effect of TUDCA on perivascular adipose tissue (PVAT) function and adiponectin release may be related to cardiovascular protection in obesity, although more studies are needed to clarify the mechanisms. Therefore, TUDCA has emerged as a potential therapeutic strategy for obesity and comorbidities.