Curcumin Mitigates the High-Fat High-Sugar Diet-Induced Impairment of Spatial Memory, Hepatic Metabolism, and the Alteration of the Gut Microbiome in Alzheimer's Disease-Induced (3xTg-AD) Mice.

The escalating prevalence of metabolic diseases and an aging demographic has been correlated with a concerning rise in Alzheimer's disease (AD) incidence. This study aimed to access the protective effects of curcumin, a bioactive flavonoid from turmeric, on spatial memory, metabolic functions, and the regulation of the gut microbiome in AD-induced (3xTg-AD) mice fed with either a normal chow diet (NCD) or a high-fat high-sugar diet (HFHSD). Our findings revealed an augmented susceptibility of the HFHSD-fed 3xTg-AD mice for weight gain and memory impairment, while curcumin supplementation demonstrated a protective effect against these changes. This was evidenced by significantly reduced body weight gain and improved behavioral and cognitive function in the curcumin-treated group. These improvements were substantiated by diminished fatty acid synthesis, altered cholesterol metabolism, and suppressed adipogenesis-related pathways in the liver, along with modified synaptic plasticity-related pathways in the brain. Moreover, curcumin enriched beneficial gut microbiota, including Oscillospiraceae and Rikenellaceae at the family level, and Oscillibacter, Alistipes, Pseudoflavonifractor, Duncaniella, and Flintibacter at the genus level. The observed alteration in these gut microbiota profiles suggests a potential crosswalk in the liver and brain for regulating metabolic and cognitive functions, particularly in the context of obesity-associated cognitive disfunction, notably AD.

Liver Oxidative Status, Serum Lipids Levels after Bariatric Surgery and High-Fat, High-Sugar Diet in Animal Model of Induced Obesity.

Nutritional status is a major determinant of hepatocyte injuries associated with changed metabolism and oxidative stress. This study aimed to determine the relations between oxidative stress, bariatric surgery, and a high-fat/high-sugar (HFS) diet in a diet-induced obesity rat model. Male rats were maintained on a control diet (CD) or high-fat/high-sugar diet (HFS) inducing obesity. After 8 weeks, the animals underwent SHAM (n = 14) or DJOS (n = 14) surgery and the diet was either changed or unchanged. Eight weeks after the surgeries, the activity of superoxide dismutase isoforms (total SOD, MnSOD, and CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and lutathione S-transferase, as well as the thiol groups (-SH) concentration, total antioxidant capacity (TAC), total oxidative stress (TOS) levels, and malondialdehyde (MDA) concentration liver tissue were assessed. The total cholesterol, triglycerides (TG), and high-density lipoprotein (HDL) concentrations were measured in the serum. The total SOD and GPX activities were higher in the SHAM-operated rats than in the DJOS-operated rats. The MnSOD activity was higher in the HFS/HFS than the CD/CD groups. Higher CuZnSOD, GST, GR activities, -SH, and MDA concentrations in the liver, and the triglyceride and cholesterol concentrations in the serum were observed in the SHAM-operated rats than in the DJOS-operated rats. The CAT activity was significantly higher in the HFS-fed rats. Lower TAC and higher TOS values were observed in the SHAM-operated rats. Unhealthy habits after bariatric surgery may be responsible for treatment failure and establishing an obesity condition with increased oxidative stress.

Metabolic mitochondrial alterations prevail in the female rat heart 8 weeks after exercise cessation.

BACKGROUND: The consumption of high-caloric diets strongly contributes to the development of non-communicable diseases (NCDs), including cardiovascular disease, the leading cause of mortality worldwide. Exercise (along with diet intervention) is one of the primary non-pharmacological approaches to promote a healthier lifestyle and counteract the rampant prevalence of NCDs. The present study evaluated the effects of exercise cessation after a short period training on the cardiac metabolic and mitochondrial function of female rats. METHODS: Seven-week-old female Sprague-Dawley rats were fed a control or a high-fat, high-sugar (HFHS) diet and, after 7 weeks, the animals were kept on a sedentary lifestyle or submitted to endurance exercise for 3 weeks (6 days per week, 20-60 min/day). The cardiac samples were analysed 8 weeks after exercise cessation. RESULTS: The consumption of the HFHS diet triggered impaired glucose tolerance, whereas the HFHS diet and physical exercise resulted in different responses in plasma adiponectin and leptin levels. Cardiac mitochondrial respiration efficiency was decreased by the HFHS diet consumption, which led to reduced ATP and increased NAD(P)H mitochondrial levels, which remained prevented by exercise 8 weeks after cessation. Exercise training-induced cardiac adaptations in redox balance, namely increased relative expression of Nrf2 and downstream antioxidant enzymes persist after an eight-week exercise cessation period. CONCLUSIONS: Endurance exercise modulated cardiac redox balance and mitochondrial efficiency in female rats fed a HFHS diet. These findings suggest that exercise may elicit cardiac adaptations crucial for its role as a non-pharmacological intervention for individuals at risk of developing NCDs.

How the Oviduct Lipidomic Profile Changes over Time after the Start of an Obesogenic Diet in an Outbred Mouse Model.

We investigated whether a high-fat/high-sugar (HF/HS) diet alters the lipidomic profile of the oviductal epithelium (OE) and studied the patterns of these changes over time. Female outbred Swiss mice were fed either a control (10% fat) or HF/HS (60% fat, 20% fructose) diet. Mice (n = 3 per treatment per time point) were sacrificed and oviducts were collected at 3 days and 1, 4, 8, 12 and 16 weeks on the diet. Lipids in the OE were imaged using matrix-assisted laser desorption ionisation mass spectrometry imaging. Discriminative m/z values and differentially regulated lipids were determined in the HF/HS versus control OEs at each time point. Feeding the obesogenic diet resulted in acute changes in the lipid profile in the OE already after 3 days, and thus even before the development of an obese phenotype. The changes in the lipid profile of the OE progressively increased and became more persistent after long-term HF/HS diet feeding. Functional annotation revealed a differential abundance of phospholipids, sphingomyelins and lysophospholipids in particular. These alterations appear to be not only caused by the direct accumulation of the excess circulating dietary fat but also a reduction in the de novo synthesis of several lipid classes, due to oxidative stress and endoplasmic reticulum dysfunction. The described diet-induced lipidomic changes suggest alterations in the OE functions and the oviductal microenvironment which may impact crucial reproductive events that take place in the oviduct, such as fertilization and early embryo development.

Age and an obesogenic diet affect mouse behaviour in a sex-dependent manner.

Obesity is rising globally and is associated with neurodevelopmental and psychiatric disorders among children, adolescents and young adults. Whether obesity is the cause or the consequence of these disorders remains unclear. To examine the behavioural effects of obesity systematically, locomotion, anxiety and social behaviour were assessed in male and female C57Bl/6J mice using the open field, elevated plus maze and social preference task. First, the effects of age and sex were examined in control mice, before investigating post-weaning consumption of a high fat-high sugar diet commonly consumed in human populations with high rates of obesity. In the open field and elevated plus maze, locomotor activity and anxiety-related behaviours reduced with aging in both sexes, but with different sex-specific profiles. The high fat-high sugar diet reduced food and calorie intake and increased body mass and fat deposition in both sexes. In the open field, both male and female mice on the obesogenic diet showed reduced locomotion; whereas, in the elevated plus maze, only females fed with the obesogenic diet displayed reduced anxiety-related behaviours. Both male and female mice on the obesogenic diet had a significantly higher social preference index than the control group. In conclusion, the findings demonstrate that the behavioural effects of age and diet-induced obesity all depend on the sex of the mouse. This emphasises the importance of considering the age of the animal and including both sexes when assessing behavioural phenotypes arising from dietary manipulations.

The Prevention of Inflammation and the Maintenance of Iron and Hepcidin Homeostasis in the Gut, Liver, and Brain Pathologies.

The human gut microbiome consists of a variety of microorganisms that inhabit the intestinal tract. This flora has recently been shown to play an important role in human disease. The crosstalk between the gut and brain axis has been investigated through hepcidin, derived from both hepatocytes and dendritic cells. Hepcidin could potentially play an anti-inflammatory role in the process of gut dysbiosis through a means of either a localized approach of nutritional immunity, or a systemic approach. Like hepcidin, mBDNF and IL-6 are part of the gut-brain axis: gut microbiota affects their levels of expression, and this relationship is thought to play a role in cognitive function and decline, which could ultimately lead to a number of neurodegenerative diseases such as Alzheimer's disease. This review will focus on the interplay between gut dysbiosis and the crosstalk between the gut, liver, and brain and how this is mediated by hepcidin through different mechanisms including the vagus nerve and several different biomolecules. This overview will also focus on the gut microbiota-induced dysbiotic state on a systemic level, and how gut dysbiosis can contribute to beginnings and the progression of Alzheimer's disease and neuroinflammation.

Despite similar clinical features metabolomics reveals distinct signatures in insulin resistant and progressively obese minipigs.

Obesity is a major contributor to the silent and progressive development of type 2 diabetes (T2D) whose prevention could be improved if individuals at risk were identified earlier. Our aim is to identify early phenotypes that precede T2D in diet-induced obese minipigs. We fed four groups of minipigs (n = 5-10) either normal-fat or high-fat high-sugar diet during 2, 4, or 6 months. Morphometric features were recorded, and metabolomics and clinical parameters were assessed on fasting plasma samples. Multivariate statistical analysis on 46 morphometrical and clinical parameters allowed to differentiate 4 distinct phenotypes: NFC (control group) and three others (HF2M, HF4M, HF6M) corresponding to the different stages of the obesity progression. Compared to NFC, we observed a rapid progression of body weight and fat mass (4-, 7-, and tenfold) in obese phenotypes. Insulin resistance (IR; 2.5-fold increase of HOMA-IR) and mild dyslipidemia (1.2- and twofold increase in total cholesterol and HDL) were already present in the HF2M and remained stable in HF4M and HF6M. Plasma metabolome revealed subtle changes of 23 metabolites among the obese groups, including a progressive switch in energy metabolism from amino acids to lipids, and a transient increase in de novo lipogenesis and TCA-related metabolites in HF2M. Low anti-oxidative capacities and anti-inflammatory response metabolites were found in the HF4M, and a perturbed hexose metabolism was observed in HF6M. Overall, we show that IR and progressively obese minipigs reveal phenotype-specific metabolomic signatures for which some of the identified metabolites could be considered as potential biomarkers of early progression to TD2.

The influence of parental high-fat high-sugar diet on the gut-brain axis in male offspring.

PURPOSE: The gut-brain axis (GBA) is implicated in the development of obesity, and its role in developmental programming needs to be explored. This study uncovers the effects of a parental high-fat, high-sugar diet (HFS) on the gut (colon) and brain (hypothalamus) GBA of male Wistar rat offspring at weaning until adulthood. METHODS: For ten weeks before mating, male progenitors were fed a control diet (CD) or HFS, whereas dams were fed CD or HFS during pregnancy and lactation. Male offspring aged 21-and 90-day old were assessed for: Gene expression of toll-like receptor 4 (TLR4) pathway and zonula occludens 1 (ZO1) in the colon and hypothalamus; hypothalamic gene expression of orexigenic neuropeptides and Leptin receptor; serum levels of lipopolysaccharide (LPS), glucagon like peptide 1 (GLP-1), Ghrelin and neuropeptide Y (NPY); colonic cytokine levels; FaecalBifidobacterium spp.andLactobacillus spp. DNA. RESULTS: Paternal HFS showed increased endotoxaemia, reduced colonic gene expression of ZO1 and reduced colonic TNF-α at weaning. In the adult offspring, paternal HFS showed increased NPY, reduced serum Ghrelin, colonic pro-inflammatory cytokines, and lower faecalBifidobacteriumspp. DNA. Maternal diet showed increased hypothalamic gene expression of myeloid differentiation primary response 88 (MYD88) at weaning. The maternal HFS diet showed increased NPY and reduced faecalBifidobacteriumspp. andLactobacillusspp. DNA in the adult offspring. The combined effect of parental diet showed increased NPY at weaning, and lowerBifidobacteriumspp. andLactobacillus spp.in the adult offspring. CONCLUSION: Maternal and paternal HFS diet seem to influence the programming of the gut-brain axis, leading to increased visceral adiposity and weight of male offspring at weaning, the effect that lasted until adulthood.

NUCB2/Nesfatin-1 Reduces Obesogenic Diet Induced Inflammation in Mice Subcutaneous White Adipose Tissue.

BACKGROUND: Excess adipose tissue accumulation and obesity are characterised by chronic, low-grade, systemic inflammation. Nestfatin-1 is a neuropeptide derived from the precursor protein nucleobindin-2 (NUCB2), which was initially reported to exert anorexigenic effects. The present study aimed to investigate the effects of an obesogenic diet (OD; high-fat, high-sugar) in NUCB2 knockout (KO) mice and of nesfatin-1 treatment in LPS-stimulated 3T3-L1 preadipocytes. METHODS: Subcutaneous white adipose tissue (Sc-WAT) samples from wild type (WT) and NUCB2 KO mice that were fed a normal diet (ND), or the OD for 12 weeks were used for RNA and protein extraction, as well as immunohistochemistry. 3T3-L1 cells were treated with 100 nM nesfatin-1 during differentiation and stimulated with 1 µg/mL LPS for measuring the expression and secretion of pro-inflammatory mediators by qPCR, western blotting, immunofluorescence, Bioplex, and ELISA. RESULTS: Following the OD, the mRNA, protein and cellular expression of pro-inflammatory mediators (Tnfα, Il-6, Il-1ß, Adgre1, Mcp1, TLR4, Hmbgb1 and NF-kB) significantly increased in the ScWAT of NUCB2 KO mice compared to ND controls. Adiponectin and Nrf2 expression significantly decreased in the ScWAT of OD-fed NUCB2 KO, without changes in the OD-fed WT mice. Furthermore, nesfatin-1 treatment in LPS-stimulated 3T3-L1 cells significantly reduced the expression and secretion of pro-inflammatory cytokines (Tnfα, Il-6, Il-1ß, Mcp1) and hmgb1. CONCLUSION: An obesogenic diet can induce significant inflammation in the ScWAT of NUCB2 KO mice, involving the HMGB1, NRF2 and NF-kB pathways, while nesfatin-1 reduces the pro-inflammatory response in LPS-stimulated 3T3-L1 cells. These findings provide a novel insight into the metabolic regulation of inflammation in WAT.

Diet leaves a genetic signature in a keystone member of the gut microbiota.

Switching from a low-fat and high-fiber diet to a Western-style high-fat and high-sugar diet causes microbiota imbalances that underlay many pathological conditions (i.e., dysbiosis). Although the effects of dietary changes on microbiota composition and functions are well documented, their impact in gut bacterial evolution remains unexplored. We followed the emergence of mutations in Bacteroides thetaiotaomicron, a prevalent fiber-degrading microbiota member, upon colonization of the murine gut under different dietary regimens. B. thetaiotaomicron evolved rapidly in the gut and Western-style diet selected for mutations that promote degradation of mucin-derived glycans. Periodic dietary changes caused fluctuations in the frequency of such mutations and were associated with metabolic shifts, resulting in the maintenance of higher intraspecies genetic diversity compared to constant dietary regimens. These results show that dietary changes leave a genetic signature in microbiome members and suggest that B. thetaiotaomicron genetic diversity could be a biomarker for dietary differences among individuals.

Parental high-fat high-sugar diet programming and hypothalamus adipose tissue axis in male Wistar rats.

PURPOSE: Maternal nutrition during early development and paternal nutrition pre-conception can programme offspring health status. Hypothalamus adipose axis is a target of developmental programming, and paternal and maternal high-fat, high-sugar diet (HFS) may be an important factor that predisposes offspring to develop obesity later in life. This study aims to investigate Wistar rats' maternal and paternal HFS differential contribution on the development, adiposity, and hypothalamic inflammation in male offspring from weaning until adulthood. METHODS: Male progenitors were fed a control diet (CD) or HFS for 10 weeks before mating. After mating, dams were fed CD or HFS only during pregnancy and lactation. Forming the following male offspring groups: CD-maternal and paternal CD; MH-maternal HFS and paternal CD; PH-maternal CD and paternal HFS; PMH-maternal and paternal HFS. After weaning, male offspring were fed CD until adulthood. RESULTS: Maternal HFS diet increased weight, visceral adiposity, and serum total cholesterol levels, and decreased hypothalamic weight in weanling male rats. In adult male offspring, maternal HFS increased weight, glucose levels, and hypothalamic NFκBp65. Paternal HFS diet lowered hypothalamic insulin receptor levels in weanling offspring and glucose and insulin levels in adult offspring. The combined effects of maternal and paternal HFS diets increased triacylglycerol, leptin levels, and hypothalamic inflammation in weanling rats, and increased visceral adiposity in adulthood. CONCLUSION: Male offspring intake of CD diet after weaning reversed part of the effects of parental HFS diet during the perinatal period. However, maternal and paternal HFS diet affected adiposity and hypothalamic inflammation, which remained until adulthood.

Sex-specific effects of metformin and liraglutide on renal pathology and expression of connexin 45 and pannexin 1 following long-term high-fat high-sugar diet.

The comparative effects of the two commonly used antidiabetic drugs metformin and liraglutide on renal pathology and expression of connexin 45 (Cx45) and pannexin 1 (Panx1) in adult obese rats fed high-fat high-sugar diet (HFHSD) were studied. Considering recent data on the profound influence of sex on metformin and liraglutide effects, we compared the effects of both drugs between male and female animals. 44-week-old Sprague-Dawley rats were separated into 4 groups that were fed: standard diet, HFHSD, HFHSD treated with metformin (s.c., 50 mg/kg/day) and HFHSD treated with liraglutide (s.c., 0.3 mg/kg/day). Treatment with metformin or liraglutide lasted for 14 weeks. Histology and immunohistochemistry were performed to quantify renal pathological changes and Cx45 and Panx1 expression. HFHSD caused thickening of the Bowman's capsule (BC). Both metformin and liraglutide failed to ameliorate the BC thickening; metformin even worsened it. Effects on the tubulointerstitial fibrosis score, BC thickness and Cx45 and Panx1 expression were sex-dependent. We found a 50% increase in mitochondria in proximal tubules of metformin- and liraglutide-treated HFHSD-fed rats, but these effects were not dependent on the sex. This is a first study showing that the effects of metformin and liraglutide on kidney pathology in rats fed HFHSD are mostly sex-dependent and that these effects are not necessarily beneficial. Both drugs changed the Cx45 and Panx 1 expression; hence their effects could be related to amelioration of disruptions in intercellular communication.

Pain in the Developing Brain: Early Life Factors Alter Nociception and Neurobiological Function in Adolescent Rats.

Although adverse early experiences prime individuals to be at increased risk for chronic pain, little research has examined the trauma-pain relationship in early life or the underlying mechanisms that drive pathology over time. Given that early experiences can potentiate the nociceptive response, this study aimed to examine the effects of a high-fat, high-sugar (HFHS) diet and early life stress (maternal separation [MS]) on pain outcomes in male and female adolescent rats. Half of the rats also underwent a plantar-incision surgery to investigate how the pain system responded to a mildly painful stimuli in adolescence. Compared with controls, animals that were on the HFHS diet, experienced MS, or had exposure to both, exhibited increased anxiety-like behavior and altered thermal and mechanical nociception at baseline and following the surgery. Advanced magnetic resonance imaging demonstrated that the HFHS diet and MS altered the maturation of the brain, leading to changes in brain volume and diffusivity within the anterior cingulate, amygdala, corpus callosum, nucleus accumbens, and thalamus, while also modifying the integrity of the corticospinal tracts. The effects of MS and HFHS diet were often cumulative, producing exacerbated pain sensitivity and increased neurobiological change. As early experiences are modifiable, understanding their role in pain may provide targets for early intervention/prevention.

N-acetylcysteine reduces addiction-like behaviour towards high-fat high-sugar food in diet-induced obese rats.

Compulsive forms of eating displayed by some obese individuals share similarities with compulsive drug-taking behaviour, a hallmark feature of substance use disorder. This raises the possibility that drug addiction treatments may show utility in the treatment of compulsive overeating. N-Acetylcysteine (NAC) is a cysteine pro-drug which has experienced some success in clinical trials, reducing cocaine, marijuana and cigarette use, as well as compulsive behaviours such as gambling and trichotillomania. We assessed the impact of NAC on addiction-like behaviour towards highly palatable food in a rat model of diet-induced obesity. Adult male Sprague-Dawley rats were placed on a high-fat high-sugar diet for 8 weeks and then assigned to diet-induced obesity-prone (DIO) or diet-induced obesity-resistant (DR) groups based on weight gain. DIO and DR rats were subjected to an operant conditioning paradigm whereby rats could lever press for high-fat high-sugar food pellets. This alternated with periods of signalled reward unavailability. Before treatment DIO rats ate more in their home cage, earned more food pellets in operant sessions, and responded more during periods that signalled reward unavailability (suggestive of compulsive-like food seeking) compared with DR rats. This persistent responding in the absence of reward displayed by DIO rats was ameliorated by daily injections of NAC (100 mg/kg, i.p.) for 14 days. By the end of the treatment period, lever-pressing by NAC-treated DIO rats resembled that of DR rats. These findings suggest that NAC reduces addiction-like behaviour towards food in rats and supports the potential use of this compound in compulsive overeating.

The effects of two types of Western diet on the induction of metabolic syndrome and cardiac remodeling in obese rats.

Metabolic syndrome (MetS) include obesity as a critical feature and is strongly associated with risk of cardiovascular disease (CVD). Insights into mechanisms involved in the pathophysiology of these clinical manifestations are essential for the development of therapeutic strategies. Thus, Western diets (WD) have been widely employed in diet-induced obesity (DIO) model. However, there are variations in fat and sugar proportions of such diets, making comparisons challenging. We aimed to assess the impact of two types of the WD on metabolic status and cardiac remodeling, to achieve a DIO model that better mimics the human pathogenesis of MetS-induced CVD. Male Wistar rats were distributed into three groups: control diet, Western diet fat (WDF), and Western diet sugar (WDS) for 41 weeks. Metabolic and inflammatory parameters and cardiac changes were characterized. WDF and WDS feeding promoted higher serum triglycerides, glucose intolerance, and insulin resistance, while just WDF presented inflammation in adipose tissue. WDF-fed rats showed increased catalase activity and malondialdehyde (MDA) and carbonyl protein levels, suggesting cardiac oxidative stress, while WDS-fed rats only raised MDA. Both WD equally elevated protein expressions involved in lipid metabolism, but only WDF downregulated the glycolysis pathway. Furthermore, the mechanical myocardial function was impaired in obese rats, being more relevant in WDF. In conclusion, both WD effectively triggered MetS features, although inflammation was detected just on the WDF-fed animals. Moreover, the WDF promoted a more pronounced functional, metabolic, and oxidative cardiac disorder, suggesting to be an adequate model for studying CVD in the scenario of MetS.

Aged Monkeys Fed a High-Fat/High-Sugar Diet Recapitulate Metabolic Disorders and Cardiac Contractile Dysfunction.

Aged nonhuman primate (NHP) models are of great value for studying the pathology of metabolic heart diseases and developing therapeutic strategies. In this study, aged male cynomolgus monkeys were fed a regular diet or a high-fat/high-sugar diet (HFSD) for 8 months. Metabolic disorders were diagnosed by 1H-NMR and serum biochemistry, and cardiac function was evaluated by echocardiography. Our results showed that serum metabolic profiles were altered in aged monkeys fed a HFSD, in line with aortic tissue damage, cardiac remodeling, and contractile dysfunction. This aged monkey model significantly increased expression of proinflammatory cytokines and altered expression and phosphorylation of intracellular signaling proteins in the heart, as compared to aged monkeys on a regular diet. Furthermore, the animals demonstrated increased phosphorylation of cardiac myofilament proteins which are causatively associated with decreased myofilament contractility. We conclude that the aged monkey model fed a HFSD exhibits metabolic disorders and cardiac contractile dysfunction.

Using intestinal flora to distinguish non-alcoholic steatohepatitis from non-alcoholic fatty liver.

OBJECTIVE: To explore specific flora in mouse models of non-alcoholic steatohepatitis (NASH) to improve NASH diagnostic protocols. METHODS: Sixty mice were divided into normal diet (ND, 20 mice) and high-fat/high-sugar diet (HFSD) groups (40 mice). After 8 weeks of feeding, 10 mice in the ND group and 20 mice in the HFSD group were sacrificed to create the short-term ND and non-alcoholic fatty liver (NAFL) groups, respectively. After 16 weeks of feeding, the remaining mice were sacrificed to create the long-term ND and NASH groups, respectively. We then examined fecal flora, serum biochemical indices, and lipopolysaccharide and tumor necrosis factor-α levels and analyzed liver tissue. RESULTS: The relative abundance of Lactobacillus, Desulfovibrio, Ruminiclostridium 9, and Turicibacter differed between NASH and NAFL mice, and the areas under the receiver operating characteristic curve of the four genera for diagnosing NASH were 0.705, 0.734, 0.737, and 0.937. The non-alcoholic fatty liver disease activity score was positively correlated with the relative abundance of Desulfovibrio (r = 0.353), Ruminiclostridium 9 (r = 0.431), and Turicibacter (r = 0.688). CONCLUSIONS: The relative abundance of Lactobacillus, Desulfovibrio, Ruminiclostridium, and Turicibacter may help distinguish NASH from NAFL.

Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice.

OBJECTIVE: Recent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as "metaflammation," which contributes to obesity and type 2 diabetes. In this study, we investigated the effects of the JAK1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine high-fat-high sugar diet model. METHODS: Male C57BL/6 mice were fed with a control normal diet (ND) or a high-fat-high sugar diet (HD) for 22 weeks. A sub-group of HD fed mice was treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks (HD + Bar). RESULTS: HD feeding resulted in obesity, insulin-resistance, hypercholesterolemia and alterations in gut microbial composition. The metabolic abnormalities were dramatically reduced by chronic baricitinib administration. Treatment of HD mice with baricitinib did not change the diet-induced alterations in the gut, but restored insulin signaling in the liver and skeletal muscle, resulting in improvements of diet-induced myosteatosis, mesangial expansion and associated proteinuria. The skeletal muscle and renal protection were due to inhibition of the local JAK2-STAT2 pathway by baricitinib. We also demonstrated that restored tissue levels of JAK2-STAT2 activity were associated with a significant reduction in cytokine levels in the blood. CONCLUSIONS: In summary, our data suggest that the JAK2-STAT2 pathway may represent a novel candidate for the treatment of diet-related metabolic derangements, with the potential for EMA- and FDA-approved JAK inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications.

Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspring.

AIMS: Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is suggested to increase the risk for cardiovascular disease. How PCOS may lead to adverse cardiac outcomes is unclear and here we hypothesized that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity in mice induce adverse metabolic and cardiac programming in female offspring that resemble the reproductive features of the syndrome. METHODS AND RESULTS: The maternal obese PCOS phenotype was induced in mice by chronic high-fat-high-sucrose consumption together with prenatal DHT exposure. The prenatally androgenized (PNA) female offspring displayed cardiac hypertrophy during adulthood, an outcome that was not accompanied by aberrant metabolic profile. The expression of key genes involved in cardiac hypertrophy was up-regulated in the PNA offspring, with limited or no impact of maternal obesity. Furthermore, the activity of NADPH oxidase, a major source of reactive oxygen species in the cardiovascular system, was down-regulated in the PNA offspring heart. We next explored for early transcriptional changes in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an up-regulation of transcription factors involved in cardiac hypertrophic remodelling and of the calcium-handling gene, Slc8a2. Finally, to determine the specific role of androgens in cardiovascular function, female mice were continuously exposed to DHT from pre-puberty to adulthood, with or without the antiandrogen flutamide. Continuous exposure to DHT led to adverse left ventricular remodelling, and increased vasocontractile responses, while treatment with flutamide partly alleviated these effects. CONCLUSION: Taken together, our results indicate that intrauterine androgen exposure programmes long-lasting heart remodelling in female mouse offspring that is linked to left ventricular hypertrophy and highlight the potential risk of developing cardiac dysfunction in daughters of mothers with PCOS.

Blue light at night acutely impairs glucose tolerance and increases sugar intake in the diurnal rodent Arvicanthis ansorgei in a sex-dependent manner.

In our modern society, the exposure to light at night (LAN) has increased considerably, which may impact human health negatively. Especially exposure to light at night containing short wavelength emissions (~450-500 nm) can disrupt the normal function of the biological clock, altering sleep-wake cycles and inducing metabolic changes. Recently, we reported that light at night acutely impairs glucose tolerance in nocturnal rats. However, light at night in nocturnal rodents coincides with their activity period, in contrast to artificial light at night exposure in humans. The aim of this study was to evaluate the acute effects of blue (λ = 490 ± 20 nm) artificial light at night (bALAN) on glucose metabolism and food intake in both male and female diurnal Sudanian grass rats (Arvicanthis ansorgei) fed either regular chow or a free choice high-fat high sucrose diet (HFHS). In both chow and HFHS fed male Arvicanthis, 1-hour of bALAN exposure induced a higher glucose response in the oral glucose tolerance test (OGTT) accompanied by a significant decrease in plasma insulin. Furthermore, in HFHS fed animals, bALAN induced an increase in sucrose intake during the dark phase in males but not in females. Additionally, 1-h of bALAN increased the nonfasted glucose levels together with plasma corticosterone in female grass rats. These results provide new and further evidence for the deleterious effects of exposure to short wavelength emission-containing artificial light at night on glucose metabolism in a diurnal rodent in a sex-dependent manner.