Endocrine FGFs and their signaling in the brain: Relevance for energy homeostasis.

Since their discovery in 2000, there has been a continuous expansion of studies investigating the physiology, biochemistry, and pharmacology of endocrine fibroblast growth factors (FGFs). FGF19, FGF21, and FGF23 comprise a subfamily with attributes that distinguish them from typical FGFs, as they can act as hormones and are, therefore, referred to as endocrine FGFs. As they participate in a broad cross-organ endocrine signaling axis, endocrine FGFs are crucial lipidic, glycemic, and energetic metabolism regulators during energy availability fluctuations. They function as powerful metabolic signals in physiological responses induced by metabolic diseases, like type 2 diabetes and obesity. Pharmacologically, FGF19 and FGF21 cause body weight loss and ameliorate glucose homeostasis and energy expenditure in rodents and humans. In contrast, FGF23 expression in mice and humans has been linked with insulin resistance and obesity. Here, we discuss emerging concepts in endocrine FGF signaling in the brain and critically assess their putative role as therapeutic targets for treating metabolic disorders.

Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing ß-cell function and survival via FGF15/19.

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, ß-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E ß-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY 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 ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E ß-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.

The bile acid TUDCA reduces age-related hyperinsulinemia in mice.

Aging is associated with glucose metabolism disturbances, such as insulin resistance and hyperinsulinemia, which contribute to the increased prevalence of type 2 diabetes (T2D) and its complications in the elderly population. In this sense, some bile acids have emerged as new therapeutic targets to treat TD2, as well as associated metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic acid (TUDCA) improves glucose homeostasis in T2D, obesity, and Alzheimer's disease mice model. However, its effects in aged mice have not been explored yet. Here, we evaluated the actions of TUDCA upon glucose-insulin homeostasis in aged C57BL/6 male mice (18-month-old) treated with 300 mg/kg of TUDCA or its vehicle. TUDCA attenuated hyperinsulinemia and improved glucose homeostasis in aged mice, by enhancing liver insulin-degrading enzyme (IDE) expression and insulin clearance. Furthermore, the improvement in glucose-insulin homeostasis in these mice was accompanied by a reduction in adiposity, associated with adipocyte hypertrophy, and lipids accumulation in the liver. TUDCA-treated aged mice also displayed increased energy expenditure and metabolic flexibility, as well as a better cognitive ability. Taken together, our data highlight TUDCA as an interesting target for the attenuation of age-related hyperinsulinemia and its deleterious effects on metabolism.

TUDCA receptors and their role on pancreatic beta cells.

Bile acids have received increasing attention over the past years as their multiple alternative roles became clearer. Tauroursodeoxycholic Acid (TUDCA) in specific has generated special interest due to its ability to promote pancreatic survival and function, as well as reduce endoplasmic reticulum stress. However, there are few studies explaining the molecular mechanisms behind TUDCA's beneficial actions on pancreatic beta cells. In this review, we decided to review the literature in order to craft a primer for researchers on what is known about TUDCA's receptors and the molecular pathways involved in this bile acid's function in the endocrine pancreas. We review the studies that focused on G protein-coupled bile acid receptor (TGR5), Sphingosine-1-phosphate receptor 2 (S1PR2) and α5ß1 Integrin function in pancreatic cells. Our hope is to provide a basis for future studies to expand upon, especially considering the current lack of studies focusing on the importance of these receptors, either through TUDCA signaling or other signaling molecules.

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer's disease mice model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Effects of growth hormone-releasing hormone agonistic analog MR-409 on insulin-secreting cells under cyclopiazonic acid-induced endoplasmic reticulum stress.

The endoplasmic reticulum (ER) stress is one of the mechanisms related to decreased insulin secretion and beta cell death, contributing to the progress of type 2 diabetes mellitus (T2D). Thus, investigating agents that can influence this process would help prevent the development of T2D. Recently, the growth-hormone-releasing hormone (GHRH) action has been demonstrated in INS-1E cells, in which it increases cell proliferation and insulin secretion. As the effects of GHRH and its agonists have not been fully elucidated in the beta cell, we proposed to investigate them by evaluating the role of the GHRH agonist, MR-409, in cells under ER stress. Our results show that the agonist was unable to ameliorate or prevent ER stress. However, cells exposed to the agonist showed less oxidative stress and greater survival even under ER stress. The mechanisms by which GHRH agonist, MR-409, leads to these outcomes require further investigation.

Resistance exercise training improves glucose homeostasis by enhancing insulin secretion in C57BL/6 mice.

Resistance exercise exerts beneficial effects on glycemic control, which could be mediated by exercise-induced humoral factors released in the bloodstream. Here, we used C57Bl/6 healthy mice, submitted to resistance exercise training for 10 weeks. Trained mice presented higher muscle weight and maximum voluntary carrying capacity, combined with reduced body weight gain and fat deposition. Resistance training improved glucose tolerance and reduced glycemia, with no alterations in insulin sensitivity. In addition, trained mice displayed higher insulinemia in fed state, associated with increased glucose-stimulated insulin secretion. Islets from trained mice showed reduced expression of genes related to endoplasmic reticulum (ER) stress, associated with increased expression of Ins2. INS-1E beta-cells incubated with serum from trained mice displayed similar pattern of insulin secretion and gene expression than isolated islets from trained mice. When exposed to CPA (an ER stress inducer), the serum from trained mice partially preserved the secretory function of INS-1E cells, and prevented CPA-induced apoptosis. These data suggest that resistance training, in healthy mice, improves glucose homeostasis by enhancing insulin secretion, which could be driven, at least in part, by humoral factors.

The bile acid TUDCA and neurodegenerative disorders: An overview.

Bear bile has been used in Traditional Chinese Medicine for thousands of years due to its therapeutic potential and clinical applications. The tauroursodeoxycholic acid (TUDCA), one of the acids found in bear bile, is a hydrophilic bile acid and naturally produced in the liver by conjugation of taurine to ursodeoxycholic acid (UDCA). Several studies have shown that TUDCA has neuroprotective action in several models of neurodegenerative disorders (ND), including Alzheimer's disease, Parkinson's disease, and Huntington's disease, based on its potent ability to inhibit apoptosis, attenuate oxidative stress, and reduce endoplasmic reticulum stress in different experimental models of these illnesses. Our research extends the knowledge of the bile acid TUDCA actions in ND and the mechanisms and pathways involved in its cytoprotective effects on the brain, providing a novel perspective and opportunities for treatment of these diseases.

The bile acid TUDCA improves glucose metabolism in streptozotocin-induced Alzheimer's disease mice model.

Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of dementia. According to predictions of the World Health Organization, more than 150 million people worldwide will suffer from dementia by 2050. An increasing number of studies have associated AD with type 2 diabetes mellitus (T2DM), since most of the features found in T2DM are also observed in AD, such as insulin resistance and glucose intolerance. In this sense, some bile acids have emerged as new therapeutic targets to treat AD and metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA), reduces amyloid oligomer accumulation and improves cognition in APP/PS1 mice model of AD, and also improves glucose-insulin homeostasis in obese and type 2 diabetic mice. Herein, we investigated the effect of TUDCA upon glucose metabolism in streptozotocin-induced AD mice model (Stz). The Stz mice that received 300 mg/kg TUDCA during 10 days (Stz + TUDCA), showed improvement in glucose tolerance and insulin sensitivity, reduced fasted and fed glycemia, increased islet mass and ß-cell area, as well as increased glucose-stimulated insulin secretion, compared with Stz mice that received only PBS. Stz + TUDCA mice also displayed lower neuroinflammation, reduced protein content of amyloid oligomer in the hippocampus, improved memory test and increased protein content of insulin receptor ß-subunit in the hippocampus. In conclusion, TUDCA treatment enhanced glucose homeostasis in the streptozotocin-induced Alzheimer's disease mice model, pointing this bile acid as a good strategy to counteract glucose homeostasis disturbance in AD pathology.

The use of the "Endocrine Circuit" as an active learning methodology to aid in the understanding of the human endocrine system.

The search for more efficient teaching methodologies is a great challenge for Brazilian educators, since most classes are still traditional (theoretical) and have little student involvement during the learning process. Active learning methodologies, where students play a central role in the learning process, are proving to be more effective and interesting when it comes to acquiring knowledge. Thus we decided to develop an innovative technique for teaching Human Endocrine Physiology, called "Endocrine Circuit." The circuit consisted of eight stations in which students were asked to organize a scheme with cards to answer a specific question about a gland or tissue with endocrine relevance. The effectiveness of the developed activity was validated through a pretest-posttest design, in which the students had to answer a 10-question test. We found out that, after the Endocrine Circuit application, students showed an improvement in the percentage of correct answers for 7 out of 10 questions contained in the questionnaire (P ≤ 0.05). In addition, the activity showed positive outcomes regarding student's engagement in this study, besides showing to be more efficient than the Brazilian traditional theoretical classes.

Impact of a playful booklet about diabetes and obesity on high school students in Campinas, Brazil.

Obesity and diabetes are two of the biggest public health problems in the modern world. One possible way to combat the rising prevalence of these diseases is through the spread of awareness about its consequences and how to prevent them. Therefore, educational interventions focused on teaching the physiological basis of these conditions might be valuable tools. However, most scholar curriculums lack high-quality material devoted to this topic. Thus we developed an educational booklet, composed of playful elements, targeted toward high school students and destined for application in classrooms. The efficacy of the developed material was validated through a pretest-posttest design, in which the students had to answer a 10-question test. After booklet completion, students had better outcomes, with an increase in the percentage of correct answers in 7 out of 10 questions contained in the test (P < 0.05). Thus we developed an effective material for usage in the high school classroom to spread the awareness of the risks of metabolic diseases and how to prevent them.

ARHGAP21 deficiency impairs hepatic lipid metabolism and improves insulin signaling in lean and obese mice.

ARHGAP21 is a Rho-GAP that controls GTPases activity in several tissues, but its role on liver lipid metabolism is unknown. Thus, to achieve the Rho-GAP role in the liver, control and ARHGAP21-haplodeficient mice were fed chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD) for 12 weeks, and pyruvate and insulin tolerance tests, insulin signaling, liver glycogen and triglycerides content, gene and protein expression, and very-low-density lipoprotein secretion were measured. Het mice displayed reduced body weight and plasma triglycerides levels, and increased liver insulin signaling. Reduced gluconeogenesis and increased glycogen content were observed in Het-HFD mice. Gene and protein expression of microsomal triglyceride transfer protein were reduced in both Het mice, while the lipogenic genes SREBP-1c and ACC were increased. ARHGAP21 knockdown resulted in hepatic steatosis through increased hepatic lipogenesis activity coupled with decreases in CPT1a expression and very-low-density lipoprotein export. In conclusion, liver of ARHGAP21-haplodeficient mice are more insulin sensitive, associated with higher lipid synthesis and lower lipid export.

Whole-Body ARHGAP21-Deficiency Improves Energetic Homeostasis in Lean and Obese Mice.

Inhibition of Rab-GAP TBC1 domain family member 1 (TBC1D1) reduces body weight and increases energy expenditure in mice. Here, we assessed the possible involvement of GTPase activating protein 21 (ARHGAP21), a Rho-GAP protein, in energy homeostasis. Wild-type and whole-body ARHGAP21-haplodeficient mice were fed either chow or high-fat diet for 10 weeks. These mice were analyzed for body weight, food intake, voluntary physical activity, and energy expenditure by indirect calorimetry. Real-time PCR was performed to determine changes in the expression of hypothalamic-anorexic genes. Whole-body ARHGAP21-haplodeficient mice showed lower body weight and food intake associated with increased energy expenditure. These mice also showed higher expression of hypothalamic-anorexic genes such as POMC and CART. Our data suggest that the reduction in body weight of ARHGAP21-haplodeficient mice was related to alterations in the central nervous system. This suggests a new role for ARHGAP21 in energetic metabolism and prompts us to consider GAP protein members as possible targets for the prevention and treatment of obesity and related diseases.

Whole body ARHGAP21 reduction improves glucose homeostasis in high-fat diet obese mice.

GTPase activating proteins (GAPs) are ubiquitously expressed, and their role in cellular adhesion and membrane traffic processes have been well described. TBC1D1, which is a Rab-GAP, is necessary for adequate glucose uptake by muscle cells, whereas increased TCGAP, which is a Rho-GAP, decreases GLUT4 translocation, and consequently glucose uptake in adipocytes. Here, we assessed the possible involvement of ARHGAP21, a Rho-GAP protein, in glucose homeostasis. For this purpose, wild type mice and ARHGAP21 transgenic whole-body gene-deficiency mice (heterozygous mice, expressing approximately 50% of ARHGAP21) were fed either chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD). Het-HFD mice showed a reduction in white fat storage, reflected in a lower body weight gain. These mice also displayed an improvement in insulin sensitivity and glucose tolerance, which likely contributed to reduced insulin secretion and pancreatic beta cell area. The reduction of body weight was also observed in Het mice and this phenomenon was associated with an increase in brown adipose tissue and reduced muscle weight, without alteration in glucose-insulin homeostasis. In conclusion, the whole body ARHGAP21 reduction improved glucose homeostasis and protected against diet-induced obesity specifically in Het-HFD mice. However, the mechanism by which ARHGAP21 leads to these outcomes requires further investigation.