Update on the transdifferentiation of pancreatic cells into functional beta cells for treating diabetes.

The increasing global prevalence and associated comorbidities need innovative approaches for type 2 diabetes mellitus (T2DM) prevention and treatment. Genetics contributes significantly to T2DM susceptibility, and genetic counseling is significant in detecting and informing people about the diabetic risk. T2DM is also intricately linked to overnutrition and obesity, and nutritional advising is beneficial to mitigate diabetic evolution. However, manipulating pancreatic cell plasticity and transdifferentiation could help beta cell regeneration and glucose homeostasis, effectively contributing to the antidiabetic fight. Targeted modulation of transcription factors is highlighted for their roles in various aspects of pancreatic cell differentiation and function, inducing non-beta cells' conversion into functional beta cells (responsive to glucose). In addition, pharmacological interventions targeting specific receptors and pathways might facilitate cell transdifferentiation aiming to maintain or increase beta cell mass and function. However, the mechanisms underlying cellular reprogramming are not yet well understood. The present review highlights the primary transcriptional factors in the endocrine pancreas, focusing on transdifferentiation as a primary mechanism. Therefore, islet cell reprogramming, converting one cell type to another and transforming non-beta cells into insulin-producing cells, depends, among others, on transcription factors. It is a promising fact that new transcription factors are discovered every day, and their actions on pancreatic islet cells are revealed. Exploring these pathways associated with pancreatic development and islet endocrine cell differentiation could unravel the molecular intricacies underlying transdifferentiation processes, exploring novel therapeutic strategies to treat diabetes. The medical use of this biotechnology is expected to be achievable within a short time.

Melatonin supplementation in obese mothers reduces hypothalamic inflammation and enhances thermogenesis in mice progeny.

Maternal obesity might induce obesity and metabolic alterations in the progeny. The study aimed to determine the effect of supplementing obese mothers with Mel (Mel) on thermogenesis and inflammation. C57BL/6 female mice (mothers) were fed from weaning to 12 weeks control diet (C, 17% kJ as fat) or a high-fat diet (HF, 49% kJ as fat) and then matted with male mice fed the control diet. Melatonin (10 mg/kg daily) was supplemented to mothers during gestation and lactation, forming the groups C, CMel, HF, and HFMel (n = 10/group). Twelve-week male offspring were studied (plasma biochemistry, immunohistochemistry, protein, and gene expressions at the hypothalamus - Hyp, subcutaneous white adipose tissue - sWAT, and interscapular brown adipose tissue - iBAT). Comparing HFMel vs. HF offspring, fat deposits and plasmatic proinflammatory markers decreased. Also, HFMel showed decreased Hyp proinflammatory markers and neuropeptide Y (anabolic) expression but improved proopiomelanocortin (catabolic) expression. Besides, HFMel sWAT adipocytes changed to a beige phenotype with-beta-3 adrenergic receptor and uncoupling protein-1 activation, concomitant with browning genes activation, triggering the iBAT thermogenic activity. In conclusion, compelling evidence indicated the beneficial effects of supplementing obese mothers with Mel on the health of their mature male offspring. Mel led to sWAT browning-related gene enhancement, increased iBAT thermogenis, and mitigated hypothalamic inflammation. Also, principal component analysis of the data significantly separated the untreated obese mother progeny from the progeny of treated obese mothers. If confirmed in humans, the findings encourage a future guideline recommending Mel supplementation during pregnancy and breastfeeding.

Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice.

The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.

Cotadutide improves brown adipose tissue thermogenesis in obese mice.

We studied the effect of cotadutide, a dual agonist glucagon-like peptide 1 (GLP1)/Glucagon, on interscapular brown adipose tissue (iBAT) remodeling and thermogenesis of obese mice. Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Then, animals were redivided, adding cotadutide treatment: C, CC, HF, and HFC for four additional weeks. The multilocular brown adipocyte structure showed fat conversion (whitening), hypertrophy, and structural disarray in the HF group, which was reverted in cotadutide-treated animals. Cotadutide enhances the body temperature, thermogenesis, and sympathetic innervation (peroxisome proliferator-activated receptor-α, ß3 adrenergic receptor, interleukin 6, and uncoupled protein 1), reduces pro-inflammatory markers (disintegrin and metallopeptidase domain, morphogenetic protein 8a, and neuregulin 4), and improves angiogenesis (vascular endothelial growth factor A, and perlecan). In addition, cotadutide enhances lipolysis (perilipin and cell death-inducing DNA fragmentation factor α), mitochondrial biogenesis (nuclear respiratory factor 1, transcription factor A mitochondrial, mitochondrial dynamin-like GTPase, and peroxisome proliferator-activated receptor gamma coactivator 1α), and mitochondrial fusion/fission (dynamin-related protein 1, mitochondrial fission protein 1, and parkin RBR E3 ubiquitin protein ligase). Cotadutide reduces endoplasmic reticulum stress (activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA-damage inducible), and extracellular matrix markers (lysyl oxidase, collagen type I α1, collagen type VI α3, matrix metallopeptidases 2 and 9, and hyaluronan synthases 1 and 2). In conclusion, the experimental evidence is compelling in demonstrating cotadutide's thermogenic effect on obese mice's iBAT, contributing to unraveling its action mechanisms and the possible translational benefits.

Obese mothers supplemented with melatonin during gestation and lactation ameliorate the male offspring's pancreatic islet cellular composition and beta-cell function.

Melatonin supplementation to obese mothers during gestation and lactation might benefit the pancreatic islet cellular composition and beta-cell function in male offspring adulthood. C57BL/6 females (mothers) were assigned to two groups (n = 20/each) based on their consumption in control (C 17% kJ as fat) or high-fat diet (HF 49% kJ as fat). Mothers were supplemented with melatonin (Mel) (10 mg/kg daily) during gestation and lactation, or vehicle, forming the groups (n = 10/each): C, CMel, HF, and HFMel. The male offspring were studied, considering they only received the C diet after weaning until three months old. The HF mothers and their offspring showed higher body weight, glucose intolerance, insulin resistance, and low insulin sensitivity than the C ones. However, HFMel mothers and their offspring showed improved glucose metabolism and weight loss than the HF ones. Also, the offspring's higher expressions of pro-inflammatory markers and endoplasmic reticulum (ER) stress were observed in HF but reduced in HFMel. Contrarily, antioxidant enzymes were less expressed in HF but improved in HFMel. In addition, HF showed increased beta-cell mass and hyperinsulinemia but diminished in HFMel. Besides, the beta-cell maturity and identity gene expressions diminished in HF but enhanced in HFMel. In conclusion, obese mothers supplemented with melatonin benefit their offspring's islet cell remodeling and function. In addition, improving pro-inflammatory markers, oxidative stress, and ER stress resulted in better glucose and insulin levels control. Consequently, pancreatic islets and functioning beta cells were preserved in the offspring of obese mothers supplemented with melatonin.

Treatment with semaglutide, a GLP-1 receptor agonist, improves extracellular matrix remodeling in the pancreatic islet of diet-induced obese mice.

AIMS: The extracellular matrix (ECM) is fundamental for the normal endocrine functions of pancreatic islet cells and plays key roles in the pathophysiology of type 2 diabetes. Here we investigated the turnover of islet ECM components, including islet amyloid polypeptide (IAPP), in an obese mouse model treated with semaglutide, a glucagon-like peptide type 1 receptor agonist. MAIN METHODS: Male one-month-old C57BL/6 mice were fed a control diet (C) or a high-fat diet (HF) for 16 weeks, then treated with semaglutide (subcutaneous 40 µg/kg every three days) for an additional four weeks (HFS). The islets were immunostained and gene expressions were assessed. KEY FINDINGS: Comparisons refer to HFS vs HF. Thus, IAPP immunolabeling and beta-cell-enriched beta-amyloid precursor protein cleaving enzyme (Bace2, -40 %) and heparanase immunolabeling and gene (Hpse, -40 %) were mitigated by semaglutide. In contrast, perlecan (Hspg2, +900 %) and vascular endothelial growth factor A (Vegfa, +420 %) were enhanced by semaglutide. Also, semaglutide lessened syndecan 4 (Sdc4, -65 %) and hyaluronan synthases (Has1, -45 %; Has2, -65 %) as well as chondroitin sulfate immunolabeling, and collagen type 1 (Col1a1, -60 %) and type 6 (Col6a3, -15 %), lysyl oxidase (Lox, -30 %) and metalloproteinases (Mmp2, -45 %; Mmp9, -60 %). SIGNIFICANCE: Semaglutide improved the turnover of islet heparan sulfate proteoglycans, hyaluronan, chondroitin sulfate proteoglycans, and collagens in the islet ECM. Such changes should contribute to restoring a healthy islet functional milieu and should reduce the formation of cell-damaging amyloid deposits. Our findings also provide additional evidence for the involvement of islet proteoglycans in the pathophysiology of type 2 diabetes.

Adult mice offspring of obese mothers supplemented with melatonin show lessened liver steatosis, inflammation, oxidative stress, and endoplasmic reticulum stress.

AIMS: To investigate, in the liver of adult offspring, the possible effects of melatonin supplementation in the obese mother during pregnancy and lactation. MAIN METHODS: C57BL/6 females were fed with a control (C) or a high-fat (HF) diet and supplemented with melatonin (Mel) during the pregnancy and lactation, forming the groups: C, CMel, HF, and HFMel. After weaning until three months old, the offspring only received the C diet. KEY FINDINGS: The HF mothers and their offspring showed higher body weight (BW) than the C mothers and offspring. However, at 3-mo-old, BW was reduced in HFMel vs. HF offspring. Also, plasmatic and liver lipid markers increased in HF vs. C offspring but were reduced in HFMel vs. HF offspring. Liver lipid content was lessened in HFMel vs. HF offspring by 50 %. Also, lipid metabolism, pro-inflammatory and endoplasmic reticulum (ER) stress genes were higher expressed in HF vs. C offspring but reduced in HFMel vs. HF offspring. Contrarily, beta-oxidation and antioxidant enzyme genes were less expressed in HF vs. C offspring but improved in HFMel vs. HF offspring. Finally, AMPK/mTOR pathway genes, initially dysregulated in the HF, were restored in the HFMel offspring. SIGNIFICANCE: The obese mother leads to liver alterations in the offspring. Current findings demonstrated the maternal melatonin supplementation during pregnancy and lactation in adult offspring's liver. Consequently, the effects were seen in mitigating the liver's AMPK/mTOR pathway genes, lipogenesis, beta-oxidation, inflammation, oxidative stress, and ER stress, preventing liver disease progression in the offspring.

Semaglutide (GLP-1 receptor agonist) stimulates browning on subcutaneous fat adipocytes and mitigates inflammation and endoplasmic reticulum stress in visceral fat adipocytes of obese mice.

Semaglutide (GLP-1 agonist) was approved for treating obesity. Although the effects on weight loss and metabolism are known, the responses of adipocytes to semaglutide are yet limited. C57BL/6 male mice (n = 20/group) were fed a control diet (C) or a high-fat (HF) diet for 16 weeks and then separated into four groups (n = 10/group) for an additional four weeks: C, C diet and semaglutide, HF, and HF diet and semaglutide. Epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (sWAT) fat pads were studied with biochemistry, immunohistochemistry/fluorescence, stereology, and reverse transcription-quantitative polymerase chain reaction. In obese mice, semaglutide reduced the fat pad masses (eWAT, -55%; sWAT, -40%), plasmatic cytokines, and proinflammatory gene expressions: tumor necrosis factor-alpha (-60%); interleukin (IL)-6 (-55%); IL-1 beta (-40%); monocyte chemoattractant protein-1 (-90%); and leptin (-80%). Semaglutide also lessened endoplasmic reticulum (ER) stress genes of activating transcription factor-4 (-85%), CCAAT enhancer-binding protein homologous protein (-55%), and growth arrest and DNA damage-inducible gene 45 (-45%). The obese mice's adipocyte hypertrophy and macrophage infiltration were equally reduced by semaglutide. Semaglutide enhanced multiloculation and uncoupled protein 1 (UCP1) labeling in obese mice: peroxisome proliferator-activated receptor-alpha (+560%) and gamma (+150%), fibronectin type III domain-containing protein 5 (+215%), peroxisome proliferator-activated receptor-alpha coactivator (+110%), nuclear respiratory factor 1 (+260%), and mitochondrial transcription factor A (+120%). Semaglutide also increased thermogenetic gene expressions for the browning phenotype maintenance: beta-3 adrenergic receptor (+520%), PR domain containing 16 (+90%), and Ucp1 (+110%). In conclusion, semaglutide showed significant beneficial effects beyond weight loss, directly on fat pads and adipocytes of obese mice, remarkably anti-inflammatory, and reduced adipocyte size and ER stress. Besides, semaglutide activated adipocyte browning, improving UCP1, mitochondrial biogenesis, and thermogenic marker expressions help weight loss.

Effects of Y1 receptor agonist on the pancreatic islet of diet-induced obese and diabetic mice.

AIMS: Agonists of the NPY receptor might be potential in protecting pancreatic islets from injury. We aimed to characterize the role of [Leu31, Pro34]-PYY, an NPYR1 agonist, in pancreatic islets of a diet-induced obesity and insulin resistance model. METHODS: We studied long-term high-fat diet intake as a model and selective agonist of the Y1 receptor to explore the pancreatic islet architecture and stereology, and insulin secretion in isolated islets and a whole animal model. Gene and protein expressions were assessed in isolated islets investigating the signaling cascades involved in inflammation, insulin signaling, and secretion. Also, the insulin release potential was studied in vitro. RESULTS: Our data reveal that an infusion of NPYR1 for 14 days did not change the body mass of mice and eating behavior. NPYR1 did not modify the islet and beta-cell mass but positively impacted the inflammatory process by lowering the expressions of Tnf alpha and If gamma. Besides, NPYR1 restored the insulin signaling and the exocytose pattern by activating the PDX1/STAT3 pathway and improving the leptin signaling cascade. CONCLUSIONS: The findings are compellingly indicating the potential effect of the NPYR1 as a target for improving the insulin resistance condition. As such, the infusion of the NPYR1 agonist would help to enhance insulin secretion by the beta-cell from the PDX1/STAT3 pathway and the improvement of the inflammatory process.

Intermittent fasting, adipokines, insulin sensitivity, and hypothalamic neuropeptides in a dietary overload with high-fat or high-fructose diet in mice.

The intermittent fasting (IF) might have benefits on metabolism and food intake. Twelve-week old C57BL/6 J mice were fed a control diet (C, 10% kcal fat), a high-fat diet (HF, 50% kcal fat) or a high-fructose diet (HFru, 50% kcal fructose) for 8 weeks, then half of the animals in each group underwent IF (24 h fed, 24 h fasting) for an additional 4 weeks. Although food intake on the fed day remained the same for all groups, all fasting groups showed a reduction in body mass compared to their counterparts. IF reduced total cholesterol, triacylglycerol, fasting glucose, fasting insulin resistance index, and plasma leptin, but increased plasma adiponectin. IF reduced Leptin gene expression in the HF-IF group, but increased proinflammatory markers in the hypothalamus, also in the C-IF group. Both groups HFru-IF and C-IF, showed alterations in the leptin signaling pathway (Leptin, OBRb, and SOCS3), mainly in the HFru-IF group, suggesting leptin resistance. NPY and POMC neuropeptides labeled the neurons of the hypothalamus by immunofluorescence, corroborating qualitatively other quantitative findings of the study. In conclusion, current results are convincing in demonstrating the IF effect on central regulation of food intake control, as shown by NPY and POMC neuropeptide expressions, resulting in a lower weight gain. Besides, IF improves glycemia, lipid metabolism, and consequently insulin and leptin resistance. However, there is increased expression of inflammatory markers in mouse hypothalamus challenged by the HF and HFru diets, which in the long term may induce adverse effects.

Anti-steatotic linagliptin pleiotropic effects encompasses suppression of de novo lipogenesis and ER stress in high-fat-fed mice.

AIM: To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice. METHODS: Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups. RESULTS: The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining. CONCLUSION: Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.

Sex-linked changes and high cardiovascular risk markers in the mature progeny of father, mother, or both father and mother consuming a high-fructose diet.

OBJECTIVES: The aim of this study was to observe the developmental origins of health and disease affecting offspring owing to the consumption of a diet containing high fructose by the father or mother or both, considering that progeny only received a control diet during postnatal life. METHODS: Male (future father) and female (future mother) C57 BL/6 mice were fed a high-fructose diet (HFru; 45% energy) or a control diet (C) for 8 wk before mating until lactation. The offspring was termed according to sex, maternal diet (first acrostic), and paternal diet (second acrostic); and received a balanced control diet until 3-mo of age when they were sacrificed. Body mass (BM), plasmatic leptin, adiponectin, uric acid, and systolic blood pressure (BP) were measured in mature offspring. RESULTS: Fasting glycemia and insulin were elevated in HFru fathers and mothers. Although there was no change in BM, fasting glycemia, or insulin of the offspring, those of HFru fathers, HFru mothers, and HFru fathers and mothers presented higher genital fat pad, leptin, uric acid, and BP, and lower adiponectin. The values of leptin and BP were maximized when both parents consumed a HFru diet. Also, there was sexual dimorphism in most of the variables, with the male offspring being affected to a greater extent than the females. CONCLUSIONS: Consumption of a fructose-rich diet by the father, the mother, or both negatively affected the adipokines, BP, and uric acid concentrations of mature offspring, with males being more affected than females. It is significant to consider that high BP and plasmatic uric acid correspond to markers of elevated cardiovascular risk in the progeny.

Browning is activated in the subcutaneous white adipose tissue of mice metabolically challenged with a high-fructose diet submitted to high-intensity interval training.

Fructose may induce an endocrine dysfunction in adipose tissue in rodents. Browning is identified by deposits of beige adipocytes in subcutaneous white adipose tissue (sWAT). We study the effects of the high-intensity interval training (HIIT) on the formation of beige adipocytes in the sWAT of mice fed a high-fructose diet. Sixty male mice (3 months old; C57BL/6) were fed two diets for 18 weeks (n=30 each): control diet (C) or high-fructose diet (F). At the 10th week, for an additional 8-week period, the groups were (n=15 each) nontrained (NT) or trained (HIIT): C-NT, C-HIIT, F-NT and F-HIIT. We evaluated body mass, energy expenditure and molecular analyses for browning and thermogenic markers in sWAT. The HIIT groups showed significantly lower body mass and increased energy expenditure. The consumption of fructose was linked with an increased sWAT mass. However, HIIT caused a reduction of sWAT mass compared to the NT groups. Energy intake was parallel in the groups, regardless of the diet type and HIIT. Fructose was related to higher glucose and insulin levels and hypertrophied sWAT adipocytes, but HIIT decreased both glucose and insulin levels and led to the appearance of brown fat-like adipocytes dispersed in sWAT with higher expression of browning markers. Also, fructose reduced the sWAT markers of mitochondrial biogenesis and beta-oxidation, which were enhanced by HIIT. In conclusion, HIIT might stimulate the sWAT browning in mice fed a high-fructose diet associated with beneficial changes in mitochondrial biogenesis and beta-oxidation markers, contributing to a whole-body metabolic improvement.

The deficiency and the supplementation of vitamin D and liver: Lessons of chronic fructose-rich diet in mice.

The fructose added to soft drinks and processed food, as well as frequent detection of vitamin D deficiency in the body, are two insults increasingly considered to cause lesions in target organs. We studied the liver after a chronic high-fructose diet deficient and supplemented with vitamin D. Sixty C57BL/6 mature male mice were allocated into six groups (n = 10) for ten weeks: control (C), control deficient in vitamin D (CDD), control supplemented with vitamin D (CDS), fructose (F), fructose deficient in vitamin D (FDD), and fructose supplemented with vitamin D (FDS). The gene expressions of vitamin D receptor and CYP27B1 and 25 hydroxyvitamin D plasma level ensured that the diets caused vitamin D deficiency or supplementation. Body mass did not change, but blood pressure (BP) increased in CDD, F, and FDD, whereas BP was controlled in FDS. Insulinemia, insulin tolerance and resistance were seen in both vitamin D deficiency and fructose groups but improved with vitamin D supplementation. The steatosis and fibrosis were observed in the CDD, F and FDD groups. Also, F and FDD showed activation of stellate cells (HSC). Lipogenesis and inflammation gene expressions were enhanced in the CDD, F and FDD groups, but diminished with vitamin D supplementation. In conclusion, we demonstrated the adverse effects of vitamin D deficiency on metabolism, liver steatosis and, combined with fructose intake, liver interstitial fibrosis with hepatic stellate cell activation, and alteration of the lipogenesis, beta-oxidation, and liver inflammation. All these data improved when vitamin D was supplemented in the animals.

Beneficial effects of intermittent fasting on steatosis and inflammation of the liver in mice fed a high-fat or a high-fructose diet.

OBJECTIVE: Intermittent fasting (IF) is a nutritional intervention with significant metabolic effects on the liver that are not yet fully understood. The aim of this study was to investigate the effects of IF on body mass, lipid profile, glucose metabolism, liver lipogenesis, ß-oxidation, and inflammation. METHODS: We used cellular and molecular techniques to investigate the effects of IF on 3-mo-old male C57 BL/6 mice that were fed control (10% kcal fat), high-fat (HF; 50% kcal fat), or high-fructose (HFr; 50% kcal fructose) diets for 8 wk. Half of the animals were submitted to IF (1 d fed, 1 d fast) for an additional 4 wk. RESULTS: Although food intake on the fed day did not differ between the groups, mice in the HF and HFr groups showed diminished body mass, total cholesterol, and triacylglycerol levels. Also, plasma adiponectin increased in the HFr group and leptin decreased in the HF mice. Oral glucose tolerance test and insulin were ameliorated by IF, regardless of the diet consumed (HF or HFr), and decreased hepatic lipogenesis and increased ß-oxidation markers, resulting in a reduction of the hepatic steatosis and inflammation. CONCLUSIONS: There were beneficial effects of IF even with the continuity of the obesogenic diet and proinflammatory diet in mice. It is recommended that based on the beneficial effects of IF on glucose and liver metabolism and inflammation that IF be a coadjutant factor in the treatment of hepatic metabolic issues and steatosis.

Pancreatic islet (of Langerhans) revisited.

One hundred and fifty years ago, Paul Langerhans described what would come to be known as pancreatic 'islet of Langerhans'. Since then, we have accumulated knowledge about the pancreatic islet, the cells that exist there and the hormones secreted by these cells. The increasing prevalence of obesity, diabetes and Alzheimer's disease in the population (three conditions that are linked to pancreatic islet function), the islet has been playing a significant role in endocrinological and metabolic studies searching how we can protect the pancreatic islet and its cell content, or how we can regenerate it. This review will be interested in the most recent and relevant aspects of knowledge regarding the pancreatic islet, always mentioning the evolution of knowledge and future perspectives for the treatment of diabetes and Alzheimer's disease. The most recent research with microRNAs and islet culture and pseudoislet culture (organoids) allows predicting advances in knowledge with new drugs to act on the islet/cells (such as the hormone glucagon-like peptide (GLP) -1) as well as induction of other islet cells like alpha-cells and delta-cells to transform into beta-cells.

Metformin enhances mitochondrial biogenesis and thermogenesis in brown adipocytes of mice.

AIMS: We studied the effect of metformin on the brown adipose tissue (BAT) in a fructose-rich-fed model, focusing on BAT proliferation, differentiation, and thermogenic markers. MAIN METHODS: C57Bl/6 mice received isoenergetic diets for ten weeks: control (C) or high-fructose (F). For additional eight weeks, animals received metformin hydrochloride (M, 250 mg/kg/day) or saline. After sacrifice, BAT and white fat pads were prepared for light microscopy and molecular analyses. KEY FINDINGS: Body mass gain, white fat pads, and adiposity index were not different among the groups. There was a reduction in energy intake in the F group and energy expenditure in the F and FM groups. Metformin led to a more massive BAT in both groups CM and FM, associated with a higher adipocyte proliferation (ß1-adrenergic receptor, proliferating cell nuclear antigen, and vascular endothelial growth factor), and differentiation (PR domain containing 16, bone morphogenetic protein 7), in part by activating 5' adenosine monophosphate-activated protein kinase. Metformin also enhanced thermogenic markers in the BAT (uncoupling protein type 1, peroxisome proliferator-activated receptor gamma coactivator-1 alpha) through adrenergic stimuli and fibroblast growth factor 21. Metformin might improve mitochondrial biogenesis in the BAT (nuclear respiratory factor 1, mitochondrial transcription factor A), lipolysis (perilipin, adipose triglyceride lipase, hormone-sensitive lipase), and fatty acid uptake (lipoprotein lipase, cluster of differentiation 36, adipocyte protein 2). SIGNIFICANCE: Metformin effects are not linked to body mass changes, but affect BAT thermogenesis, mitochondrial biogenesis, and fatty acid uptake. Therefore, BAT may be a metformin adjuvant target for the treatment of metabolic disorders.

Administration of eicosapentaenoic and docosahexaenoic acids may improve the remodeling and browning in subcutaneous white adipose tissue and thermogenic markers in brown adipose tissue in mice.

The role of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in browning and thermogenesis has not been fully elucidated. Thus, we meant to evaluate the effect of EPA and DHA, administered alone or combined, with the activation of browning markers in subcutaneous white adipose tissue (sWAT), and thermogenic markers in brown adipose tissue (BAT). C57BL/6 adult male mice received a control diet or a high-fructose diet (HFru) for eight weeks, but after the first three weeks, HFru was divided into new groups: HFru, HFru + EPA, HFru + DHA, and HFru-EPA + DHA. EPA and DHA diminished adipocyte hypertrophy, recovered markers of browning in sWAT and thermogenic factors in the BAT, and improved gene expressions linked with mitochondrial biogenesis and lipid metabolism. Importantly, EPA and DHA administrated alone showed stronger results than the combination of EPA + DHA. The results suggest that EPA and DHA might be useful as adjuvant strategies to treat metabolic-associated disorders.

Vitamin D deficiency aggravates the liver metabolism and inflammation in ovariectomized mice.

AIMS: A prevalence of vitamin D deficiency has been reported in association with the postmenopause. Thus, we aimed to experimentally study the effect of the vitamin D deficiency and ovariectomy, alone or combined, in the liver damage. MAIN METHODS: Three-months-old female mice C57BL/6 with bilateral ovariectomy (Ovx group, n = 30) or a sham procedure (n = 30) were separated feeding control diet (C, n = 15) or a diet restricted in vitamin D (D-, n = 15) during additional 12 weeks. KEY FINDINGS: Body mass (BM) and blood pressure (BP) were higher in Ovx than in C animals, but highest in Ovx (D-) that also showed glucose intolerance/ insulin resistance. Plasmatic lipids, alanine aspartase transferase, and hepatic steatosis were increased because of the combination of Ovx and D-. However, D- had little implication in the changes of the BM and BP, but affected hepatic steatosis. Gene and protein expressions demonstrated an impaired glucose uptake in the liver because of Ovx and D-, and an increase in lipogenesis and decrease in beta-oxidation in the liver associated more to the Ovx, but also evident in D-. Also, interleukin 6 and tumor necrosis factor alpha showed an enhancement due to dietary restriction of vitamin D. SIGNIFICANCE: The findings demonstrated that ovariectomy and dietary restriction of vitamin D are inducers of harmful effects on the liver of mice, enhancing lipogenesis and inflammation and compromising beta-oxidation. The treatment of vitamin D deficiency is simple and not costly and can reduce the impact of menopause on metabolism and especially the liver.

Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies / Pais obesos levam a metabolismo alterado e obesidade em seus filhos na idade adulta: revisão de estudos experimentais e humanos

Abstract Objective: To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children. Sources: A non-systematic review in the PubMed database found few publications in which paternal obesity was implicated in the adverse transmission of characteristics to offspring. Specific articles on epigenetics were also evaluated. As the subject is recent and still controversial, all articles were considered regardless of year of publication. Summary of findings: Studies in humans and animals have established that paternal obesity impairs their hormones, metabolism, and sperm function, which can be transmitted to their offspring. In humans, paternal obesity results in insulin resistance/type 2 diabetes and increased levels of cortisol in umbilical cord blood, which increases the risk factors for cardiovascular disease. Notably, there is an association between body fat in parents and the prevalence of obesity in their daughters. In animals, paternal obesity led to offspring alterations on glucose-insulin homeostasis, hepatic lipogenesis, hypothalamus/feeding behavior, kidney of the offspring; it also impairs the reproductive potential of male offspring with sperm oxidative stress and mitochondrial dysfunction. An explanation for these observations (human and animal) is epigenetics, considered the primary tool for the transmission of phenotypes from the father to offspring, such as DNA methylation, histone modifications, and non-coding RNA. Conclusions: Paternal obesity can induce programmed phenotypes in offspring through epigenetics. Therefore, it can be considered a public health problem, affecting the children's future life.

Resumo Objetivo: Discutir a literatura recente sobre obesidade paterna, focalizando os possíveis mecanismos de transmissão dos fenótipos do pai para os filhos. Fontes: Uma revisão não-sistemática no banco de dados PubMed encontrou poucas publicações com obesidade paterna implicada com a transmissão adversa das características à prole. Artigos específicos sobre epigenética também foram avaliados. Como o assunto é recente e ainda controverso, todos os trabalhos foram considerados independentemente do ano de publicação. Resumo dos achados: Estudos em seres humanos e animais estabeleceram que a obesidade do pai prejudica seus hormônios, metabolismo e função espermática, que pode ser transmitida à prole. Em humanos, a obesidade paterna resulta em resistência à insulina / diabetes tipo 2 e aumento do nível de cortisol no sangue do cordão umbilical, que aumenta os fatores de risco para doença cardiovascular. Notavelmente, existe associação entre a gordura corporal nos pais e a prevalência de obesidade em suas filhas. Em animais, pais obesos condicionam, na prole, a homeostase glicose-insulina, lipogênese hepática, hipotálamo / comportamento alimentar, rim, prejudicam o potencial reprodutivo da prole masculina com estresse oxidativo espermático e disfunção mitocondrial. Uma explicação para estas observações (humanos e animais) é a epigenética, considerada a ferramenta básica para a transmissão de fenótipos do pai à prole, como a metilação do DNA, modificações nas histonas, e RNA não codificante. Conclusões: A obesidade paterna pode induzir fenótipos programados na prole através da epigenética. Portanto, a obesidade paterna pode ser considerada um problema de saúde pública, afetando a vida futura das crianças.