Prenatal Choline Supplementation Improves Glucose Tolerance and Reduces Liver Fat Accumulation in Mouse Offspring Exposed to Ethanol during the Prenatal and Postnatal Periods.

Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber-DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha (Ppara) and low-density lipoprotein receptor (Ldlr), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice.

Mechanisms by which sheep milk consumption ameliorates insulin resistance in high-fat diet-fed mice.

Sheep milk is rich in fat, protein, vitamins and minerals and is also one of the most important sources of natural bioactives. Several biopeptides in sheep milk have been reported to possess antibacterial, antiviral and anti-inflammatory properties, and they may prevent type 2 diabetes (T2D), disease and cancer. However, the precise mechanism(s) underlying the protective role of sheep milk against T2D development remains unclear. Therefore, in the current study, we investigated the effect of sheep milk on insulin resistance and glucose intolerance in high-fat diet (HFD)-fed mice, by conducting intraperitoneal glucose tolerance tests, metabolic cage studies, genomic sequencing, polymerase chain reaction, and biochemical assays. Hyperinsulinemic-euglycemic clamp-based experiments revealed that mice consuming sheep milk exhibited lower hepatic glucose production than mice in the control group. These findings further elucidate the mechanism by which dietary supplementation with sheep milk alleviates HFD-induced systemic glucose intolerance.

Effect of (poly)phenol-rich 'Daux Belan' apple supplementation on diet-induced obesity and glucose intolerance in C57BL/6NCrl mice.

Obesity is a state of metabolic dysfunction that can lead to dyslipidemia and impaired glucose homeostasis. Apple polyphenols have been shown to ameliorate dyslipidemia/metabolic dysfunction in humans. The influence of apple (poly)phenols on energy metabolism in high-fat (HF) diet-induced obese mice remains controversial. This study examined the effect of dietary supplementation of (poly)phenol-rich 'Daux Belan' apple (DB; 6.2 mg gallic acid equivalence (GAE)/mouse/day; 0.15% (poly)phenol) in the form of freeze-dried powder on glucose and lipid metabolism in male HF-fed C57BL/6NCrl mice, in comparison to low-(poly)phenol-containing 'Zestar' apple (Z; 0.4 mg GAE/mouse/day). Obesity, glucose intolerance, hypertriglyceridemia, and hepatic lipid vacuolation were induced by HF feeding while circulating cholesterol levels remained unchanged. DB apple supplementation did not protect against HF-induced body weight gain, hyperglycemia, hepatic triglyceride level elevation, and hepatic lipid vacuolation at the tested dosage. Future studies should be conducted with increased DB dosage and employ apple (poly)phenols supplemented in the form of extracts or sugar-free powder.

Characterization of lipid signatures in the plasma and insulin-sensitive tissues of the C57BL/6J mice fed on obesogenic diets.

Diet-induced obesity mouse models are widely utilized to investigate the underlying mechanisms of dyslipidemia, glucose intolerance, insulin resistance, hepatic steatosis, and type 2 diabetes mellitus (T2DM), as well as for screening potential drug compounds. However, there is limited knowledge regarding specific signature lipids that accurately reflect dietary disorders. In this study, we aimed to identify key lipid signatures using LC/MS-based untargeted lipidomics in the plasma, liver, adipose tissue (AT), and skeletal muscle tissues (SKM) of male C57BL/6J mice that were fed chow, LFD, or obesogenic diets (HFD, HFHF, and HFCD) for a duration of 20 weeks. Furthermore, we conducted a comprehensive lipid analysis to assess similarities and differences with human lipid profiles. The mice fed obesogenic diets exhibited weight gain, glucose intolerance, elevated BMI, glucose and insulin levels, and a fatty liver, resembling characteristics of T2DM and obesity in humans. In total, we identified approximately 368 lipids in plasma, 433 in the liver, 493 in AT, and 624 in SKM. Glycerolipids displayed distinct patterns across the tissues, differing from human findings. However, changes in sphingolipids, phospholipids, and the expression of inflammatory and fibrotic genes showed similarities to reported human findings. Significantly modulated pathways in the obesogenic diet-fed groups included ceramide de novo synthesis, sphingolipid remodeling, and the carboxylesterase pathway, while lipoprotein-mediated pathways were minimally affected. This study provides a tissue-specific comparison of lipid composition, highlighting the usefulness of DIO models in preclinical research. However, caution is warranted when extrapolating findings from these models to dyslipidemia-associated pathologies and their complications in humans.

Saturated Fatty Acids and Omega-3 Polyunsaturated Fatty Acids Improve Metabolic Parameters in Ovariectomized Female Mice.

In menopausal and postmenopausal women, the risk for obesity, cardiovascular disease, osteoporosis, and gut dysbiosis are elevated by the depletion of 17ß-estradiol. A diet that is high in omega-6 polyunsaturated fatty acids (PUFAs), particularly linoleic acid (LA), and low in saturated fatty acids (SFAs) found in coconut oil and omega-3 PUFAs may worsen symptoms of estrogen deficiency. To investigate this hypothesis, ovariectomized C57BL/6J and transgenic fat-1 mice, which lower endogenous omega-6 polyunsaturated fatty acids, were treated with either a vehicle or estradiol benzoate (EB) and fed a high-fat diet with a high or low PUFA:SFA ratio for ~15 weeks. EB treatment reversed obesity, glucose intolerance, and bone loss in ovariectomized mice. fat-1 mice fed a 1% LA diet experienced reduced weight gain and adiposity, while those fed a 22.5% LA diet exhibited increased energy expenditure and activity in EB-treated ovariectomized mice. Coconut oil SFAs and omega-3 FAs helped protect against glucose intolerance without EB treatment. Improved insulin sensitivity was observed in wild-type and fat-1 mice fed 1% LA diet with EB treatment, while fat-1 mice fed 22.5% LA diet was protected against insulin resistance without EB treatment. The production of short-chain fatty acids by gut microbial microbiota was linked to omega-3 FAs production and improved energy homeostasis. These findings suggest that a balanced dietary fatty acid profile containing SFAs and a lower ratio of omega-6:omega-3 FAs is more effective in alleviating metabolic disorders during E2 deficiency.

Dietary Nitrate and Corresponding Gut Microbiota Prevent Cardiac Dysfunction in Obese Mice.

Impaired heart function can develop in individuals with diabetes in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal bacteria are important for metabolism of nitrate, we examined whether dietary nitrate and fecal microbial transplantation (FMT) from nitrate-fed mice could prevent high-fat diet (HFD)-induced cardiac abnormalities. Male C57Bl/6N mice were fed a low-fat diet (LFD), HFD, or HFD+Nitrate (4 mmol/L sodium nitrate) for 8 weeks. HFD-fed mice presented with pathological left ventricle (LV) hypertrophy, reduced stroke volume, and increased end-diastolic pressure, in association with increased myocardial fibrosis, glucose intolerance, adipose inflammation, serum lipids, LV mitochondrial reactive oxygen species (ROS), and gut dysbiosis. In contrast, dietary nitrate attenuated these detriments. In HFD-fed mice, FMT from HFD+Nitrate donors did not influence serum nitrate, blood pressure, adipose inflammation, or myocardial fibrosis. However, microbiota from HFD+Nitrate mice decreased serum lipids, LV ROS, and similar to FMT from LFD donors, prevented glucose intolerance and cardiac morphology changes. Therefore, the cardioprotective effects of nitrate are not dependent on reducing blood pressure, but rather mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis. ARTICLE HIGHLIGHTS: Identifying therapeutic approaches that prevent cardiometabolic diseases are clearly important, and nitrate represents one such potential compound given its multifactorial metabolic effects. We aimed to determine whether nitrate could prevent high-fat diet (HFD)-induced cardiac abnormalities and whether this was dependent on the gut microbiome. Dietary nitrate attenuated HFD-induced pathological changes in cardiac remodelling, left ventricle reactive oxygen species, adipose inflammation, lipid homeostasis, glucose intolerance, and gut dysbiosis. Fecal microbial transplantation from nitrate-fed mice also prevented serum dyslipidemia, left ventricle reactive oxygen species, glucose intolerance, and cardiac dysfunction. Therefore, the cardioprotective effects of nitrate are related to mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis.

Active Glycogen Synthase in the Liver Prevents High-Fat Diet-Induced Glucose Intolerance, Decreases Food Intake, and Lowers Body Weight.

Many lines of evidence demonstrate a correlation between liver glycogen content and food intake. We previously demonstrated that mice overexpressing protein targeting to glycogen (PTG) specifically in the liver-which have increased glycogen content in this organ-are protected from high-fat diet (HFD)-induced obesity by reduced food intake. However, the use of PTG to increase liver glycogen implies certain limitations. PTG stimulates glycogen synthesis but also inhibits the enzyme responsible for glycogen degradation. Furthermore, as PTG is a regulatory subunit of protein phosphatase 1 (PP1), which regulates many cellular functions, its overexpression could have side effects beyond the regulation of glycogen metabolism. Therefore, it is necessary to determine whether the direct activation of glycogen synthesis, without affecting its degradation or other cellular functions, has the same effects. To this end, we generated mice overexpressing a non-inactivatable form of glycogen synthase (GS) specifically in the liver (9A-MGSAlb mice). Control and 9a-MGSAlb mice were fed a standard diet (SD) or HFD for 16 weeks. Glucose tolerance and feeding behavior were analyzed. 9A-MGSAlb mice showed an increase in hepatic glycogen in fed and fasting conditions. When fed an HFD, these animals preserved their hepatic energy state, had a reduced food intake, and presented a lower body weight and fat mass than control animals, without changes in energy expenditure. Furthermore, 9A-MGSAlb animals showed improved glucose tolerance when fed an SD or HFD. Moreover, liver triacylglycerol levels that were increased after HFD feeding were lower in these mice. These results confirm that increased liver glycogen stores contribute to decreased appetite and improve glucose tolerance in mice fed an HFD. On the basis of our findings, strategies to preserve hepatic glycogen stores emerge as potential treatments for obesity and hyperglycemia.

Long-chain n-3 PUFA given before and throughout gestation and lactation in rats prevent high-fat diet-induced insulin resistance in male offspring in a tissue-specific manner.

This study investigated whether long-chain n-3 PUFA (LC n-3 PUFA) given to pregnant rats fed a high-fat (HF) diet may prevent fetal programming in male offspring at adulthood. Six weeks before mating, and throughout gestation and lactation, female nulliparous Sprague-Dawley rats were given a chow (C) diet, HF (60·6 % fat from maize, rapeseed oils and lard) or HF in which one-third of fat was replaced by fish oil (HF n-3). At weaning, the three offspring groups were randomly separated in two groups fed C diet, or HF without LC n-3 PUFA, for 7 weeks until adulthood. Glucose tolerance and insulin sensitivity were assessed by an oral glucose tolerance test both at weaning and at adulthood. Insulin signalling was determined in liver, muscle and adipose tissue by quantification of the phosphorylation of Akt on Ser 473 at adulthood. At weaning, as at adulthood, offspring from HF-fed dams were obese and displayed glucose intolerance (GI) and insulin resistance (IR), but not those from HFn-3 fed dams. Following the post-weaning C diet, phosphorylation of Akt was strongly reduced in all tissues of offspring from HF dams, but to a lesser extent in liver and muscle of offspring from HFn-3 dams. However, it was abolished in all tissues of all offspring groups fed the HF post-weaning diet. Thus, LC n-3 PUFA introduced in a HF in dams partially prevented the transmission of GI and IR in adult offspring even though they were fed without LC n-3 PUFA from weaning.

Myricetin derivative-rich fraction from Syzygium malaccense prevents high-fat diet-induced obesity, glucose intolerance and oxidative stress in C57BL/6J mice.

AIM: A high-fat diet (HFD) can lead to obesity and related metabolic disorders. This study evaluated the preventive efficacy of myricetin derivative-rich fraction (MD) from Syzygium malaccense leaf extract against HFD-induced obesity, hyperglycaemia, and oxidative stress in C57BL/6J mice. METHODS: HFD-fed mice were administered MD (50 mg/kg, 100 mg/kg, and 150 mg/kg) or 2 mg/kg metformin (positive control) orally for 16 weeks. Normal diet and HFD-fed control groups received normal saline. RESULTS: MD dose of 50 mg/kg was better than 100 mg/kg and 150 mg/kg in significantly reducing weight-gain, glucose intolerance, insulin resistance, lipid accumulation in liver and kidney, and improving the serum lipid profile. Lowered protein carbonyls and lipid hydroperoxides in urine and tissue homogenates and elevated reduced glutathione, ferric reducing antioxidant power (FRAP), and Trolox equivalent antioxidant capacity (TEAC) levels in tissue homogenates indicated amelioration of oxidative stress. CONCLUSION: MD has therapeutic value in the prevention and management of obesity, hyperglycaemia, and oxidative stress.

Canary Seed (Phalaris canariensis L.) Peptides Prevent Obesity and Glucose Intolerance in Mice Fed a Western Diet.

Previous research showed that canary seed (Phalaris canariensis L.) peptides (CSP) possess robust in vitro antiobesity properties via inhibition of pancreatic lipase (PL). Nevertheless, no studies have yet explored their antiobesity properties in vivo. Consequently, we investigated the effects of CSP in C57BL/6J mice under a Western diet (WD). Mice were assigned into groups and fed a normal diet (ND) or a WD accompanied by an oral dose of CSP (250 or 500 mg/kg/day), orlistat (40 mg/kg/day), or distilled water. The results showed that consuming CSP can provide metabolic benefits, including preventing weight gain by up to 20%, increasing glucose tolerance, and reducing insulin, leptin, and LDL/VLDL levels in plasma. Conversely, total ghrelin was unaffected by CSP-500, but decreased by CSP-250, and amplified by orlistat. Surprisingly, CSP-250 was more effective in preventing weight gain and promoting satiety than CSP-500. Parallel to this, protein absorption in CSP-500 was decreased, supported by a rise in fecal crude protein (+3.5%). Similarly, fecal fat was increased by orlistat (38%) and was unaffected by CSP-250 (3.0%) and CSP (3.0%), comparatively to WD (2.5%). Despite this, both CSP treatments were equally effective in decreasing hepatic steatosis and avoiding hyperlipidemia. Furthermore, the enzymatic analysis showed that CSP-PL complexes dissociated faster (15 min) than orlistat-PL complexes (41 min). Lastly, CSP did not affect expression of hepatic lipid oxidation genes ACO and PPAR-α, but reduced the expression of the hydrolase gene LPL, and lipogenesis related genes FAS and ACC. Taken together, these results suggest that CSP antiobesity mechanism relies on lipid metabolism retardation to increase fat transit time and subsequently suppress hunger.

Human CIDEC transgene improves lipid metabolism and protects against high-fat diet-induced glucose intolerance in mice.

Cell death-inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in high-fat diet-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans, and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential 'drug' or a 'druggable' target to reverse obesity-induced lipotoxicity and glucose intolerance.

Normalization of maternal adiponectin in obese pregnant mice prevents programming of impaired glucose metabolism in adult offspring.

Infants born to obese mothers have a greater risk for childhood obesity and insulin resistance. However, the underlying biological mechanism remains elusive, which constitutes a significant roadblock for developing specific prevention strategies. Maternal adiponectin levels are lower in obese pregnant women, which is linked with increased placental nutrient transport and fetal overgrowth. We have previously reported that adiponectin supplementation to obese dams during the last four days of pregnancy prevented the development of obesity, glucose intolerance, muscle insulin resistance, and fatty liver in three months old offspring. In the present study, we tested the hypothesis that 6-9-month-old offspring of obese dams show glucose intolerance associated with muscle insulin resistance and mitochondrial dysfunction and that normalization of maternal adiponectin in obese pregnant mice prevents the development of this phenotype in the offspring. Male and female offspring of obese mice exhibited in vivo glucose intolerance and insulin resistance at 6 and 9 months of age. In gastrocnemius muscles ex vivo, male and female offspring of obese dams showed reduced phosphorylation of insulin receptor substrate 1Tyr-608 , AktThr-308 , and decreased Glut4 plasma membrane translocation upon insulin stimulation. These metabolic abnormalities in offspring born to obese mice were largely prevented by normalization of maternal adiponectin levels in late pregnancy. We provide evidence that low circulating maternal adiponectin is a critical mechanistic link between maternal obesity and the development of metabolic disease in offspring. Strategies aimed at improving maternal adiponectin levels may prevent long-term metabolic dysfunction in offspring of obese mothers.

Brown adipose tissue prevents glucose intolerance and cardiac remodeling in high-fat-fed mice after a mild myocardial infarction.

BACKGROUND: Obesity increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes (T2D) after myocardial infarction (MI). Brown adipose tissue (BAT) is important to combat obesity and T2D, and increasing BAT mass by transplantation improves glucose metabolism and cardiac function. The objective of this study was to determine if BAT had a protective effect on glucose tolerance and cardiac function in high-fat diet (HFD) fed mice subjected to a mild MI. METHODS: Male C57BL/6 mice were fed a HFD for eight weeks and then divided into Sham (Sham-operated) and +BAT (mice receiving 0.1 g BAT into their visceral cavity). Sixteen weeks post-transplantation, mice were further subdivided into ±MI (Sham; Sham-MI; +BAT; +BAT-MI) and maintained on a HFD. Cardiac (echocardiography) and metabolic function (glucose and insulin tolerance tests, body composition and exercise tolerance) were assessed throughout 22 weeks post-MI. Quantitative PCR (qPCR) was performed to determine the expression of genes related to metabolic function of perigonadal adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), liver, heart, tibialis anterior skeletal muscle (TA); and BAT. RESULTS: +BAT prevented the increase in left ventricle mass (LVM) and exercise intolerance in response to MI. Similar to what is observed in humans, Sham-MI mice developed IGT post-MI, but this was negated in +BAT-MI mice. IGT was independent of changes in body composition. Genes involved in inflammation, insulin resistance, and metabolism were significantly altered in pgWAT, scWAT, and liver in Sham-MI mice compared to all other groups. CONCLUSIONS: BAT transplantation prevents IGT, the increase in LVM, and exercise intolerance following MI. MI alters the expression of several metabolic-related genes in WAT and liver in Sham-MI mice, suggesting that these tissues may contribute to the impaired metabolic response. Increasing BAT may be an important intervention to prevent the development of IGT or T2D and cardiac remodeling in obese patients post-MI.

Fortifying a meal with oyster mushroom powder beneficially affects postprandial glucagon-like peptide-1, non-esterified free fatty acids and hunger sensation in adults with impaired glucose tolerance: a double-blind randomized controlled crossover trial.

PURPOSE: Impaired glucose tolerance (IGT) is a pathophysiological condition characterized by insulin resistance with known metabolic consequences such as postprandial hyperglycemia and hypertriglyceridemia. We hypothesized that fortifying a meal with mushrooms rich in ß-glucans may diminish glucose and triglyceride responses by improving postprandial gastrointestinal hormone release. METHODS: In a randomized controlled crossover study, 22 subjects with IGT ingested a meal either enriched with 20 g powder (8.1 g ß-glucans) of oven-dried Pleurotus ostreatus (enriched meal, EN) or without enrichment (control meal, CON). Blood was collected before and repeatedly within 4 h after the meal to determine AUC of glucose (primary outcome), insulin, triglycerides, non-esterified free fatty acids (NEFAs), glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and ghrelin. Appetite sensations (hunger, satiety, fullness, and desire to eat) were assessed before and after meal consumption by visual analog scales. RESULTS: Postprandial glucose, insulin, triglycerides, GIP and ghrelin concentrations as well as the corresponding AUCs did not differ between EN and CON. NEFAs-AUC was 14% lower (P = 0.026) and GLP-1-AUC 17% higher (P = 0.001) after EN compared to CON. Appetite ratings did not differ between treatments, except for hunger (AUC 22% lower after EN vs. CON; P = 0.031). CONCLUSION: The observed immediate postprandial metabolic changes indicate that an easily manageable fortification of a single meal with powder from dried oyster mushrooms as ß-glucan source may improve postprandial metabolism. If the effect is preserved long term, this measure can diminish the risk for further development of overweight/obesity and type 2 diabetes in subjects with IGT. CLINICAL TRIAL REGISTRATION: German Clinical Trial Register on 09/08/2018; trial-ID: DRKS00015244.

Deficiency of M-LP/Mpv17L leads to development of ß-cell hyperplasia and improved glucose tolerance via activation of the Wnt and TGF-ß pathways.

M-LP/Mpv17L is a protein that was initially identified during screening of age-dependently expressed genes in mice. We have recently demonstrated that M-LP/Mpv17L-knockout (M-LP/Mpv17L-KO) in human hepatoma cells leads to a reduction of cellular cyclic nucleotide phosphodiesterase (PDE) activity, and that in vitro-synthesized M-LP/Mpv17L possesses PDE activity. These findings suggest that M-LP/Mpv17L functions as an atypical PDE, even though it has none of the well-conserved catalytic region or other structural motifs characteristic of the PDE family. In this study, we found that M-LP/Mpv17L-KO mice developed ß-cell hyperplasia and improved glucose tolerance. Deficiency of M-LP/Mpv17L in islets from KO mice at early postnatal stages or siRNA-mediated suppression of M-LP/Mpv17L in rat insulinoma cells led to marked upregulation of lymphoid enhancer binding factor 1 (Lef1) and transcription factor 7 (Tcf7), key nuclear effectors in the Wnt signaling pathway, and some of the factors essential for the development and maintenance of ß-cells. Moreover, at the protein level, increases in the levels of phosphorylated ß-catenin and glycogen synthase kinase-3ß (GSK-3ß) were observed, indicating activation of the Wnt and TGF-ß signaling pathways. Taken together, these findings suggest that protein kinase A (PKA)-dependent phosphorylations of ß-catenin and GSK-3ß, the key mediators of the Wnt and/or TGF-ß signaling pathways, are the most upstream events triggering ß-cell hyperplasia and improved glucose tolerance caused by M-LP/Mpv17L deficiency.

Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic ß cell function in type 2 diabetes.

Pancreatic ß cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the ß cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in ß cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM ß cells contributes to ß cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in ß cells of patients with T2DM and demonstrated that its expression was associated with loss of ß cell transcriptional identity, intracellular alkalinization, and ß cell dysfunction. In addition, we generated a ß cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and ß cell dysfunction. Importantly, improved glucose tolerance and enhanced ß cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating ß cell identity and function. These results suggest that increased ß cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of ß cell failure and should be considered as a potential therapeutic target.

Caloric Restriction per se Rather Than Dietary Macronutrient Distribution Plays a Primary Role in Metabolic Health and Body Composition Improvements in Obese Mice.

Caloric restriction (CR) is of key importance in combating obesity and its associated diseases. We aimed to examine effects of dietary macronutrient distribution on weight loss and metabolic health in obese mice exposed to CR. Male C57BL/6J mice underwent diet-induced obesity for 18 weeks. Thereafter mice were exposed to a 6-week CR for up to 40% on either low-fat diet (LFD; 20, 60, 20% kcal from protein, carbohydrate, fat), low-carb diet (LCD; 20, 20, 60% kcal, respectively) or high-pro diet (HPD; 35, 35, 30% kcal, respectively) (n = 16 each). Ten mice on the obesogenic diet served as age-matched controls. Body composition was evaluated by tissue dissections. Glucose tolerance, bloods lipids and energy metabolism were measured. CR-induced weight loss was similar for LFD and LCD while HPD was associated with a greater weight loss than LCD. The diet groups did not differ from obese controls in hindlimb muscle mass, but showed a substantial decrease in body fat without differences between them. Glucose tolerance and blood total cholesterol were weight-loss dependent and mostly improved in LFD and HPD groups during CR. Blood triacylglycerol was lowered only in LCD group compared to obese controls. Thus, CR rather than macronutrient distribution in the diet plays the major role for improvements in body composition and glucose control in obese mice. Low-carbohydrate-high-fat diet more successfully reduces triacylglycerol but not cholesterol levels compared to isocaloric high-carbohydrate-low-fat weight loss diets.

Treatment with atrial natriuretic peptide induces adipose tissue browning and exerts thermogenic actions in vivo.

Increasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported A-type NP (ANP) raises intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether exogenous ANP-treatment exerts a significant impact on adipose tissues in vivo. Mice fed a high-fat-diet (HFD) or normal-fat-diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. ANP-treatment significantly ameliorated HFD-induced insulin resistance. HFD increased brown adipose tissue (BAT) cell size with the accumulation of lipid droplets (whitening), which was suppressed by ANP-treatment (re-browning). Furthermore, HFD induced enlarged lipid droplets in inguinal white adipose tissue (iWAT), crown-like structures in epididymal WAT, and hepatic steatosis, all of which were substantially attenuated by ANP-treatment. Likewise, ANP-treatment markedly increased UCP1 expression, a specific marker of BAT, in iWAT (browning). ANP also further increased UCP1 expression in BAT with NFD. Accordingly, cold tolerance test demonstrated ANP-treated mice were tolerant to cold exposure. In summary, exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis and by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.

Nicotinamide riboside has minimal impact on energy metabolism in mouse models of mild obesity.

Supplementation with precursors of NAD has been shown to prevent and reverse insulin resistance, mitochondrial dysfunction, and liver damage in mouse models of diet-induced obesity. We asked whether the beneficial effects of supplementation with the NAD precursor nicotinamide riboside (NR) are dependent on mouse strain. We compared the effects of NR supplementation on whole-body energy metabolism and mitochondrial function in mildly obese C57BL/6N and C57BL/6J mice, two commonly used strains to investigate metabolism. Male C57BL/6N and C57BL/6J mice were fed a high-fat diet (HFD) or standard chow with or without NR supplementation for 8 weeks. Body and organ weights, glucose tolerance, and metabolic parameters as well as mitochondrial O2 flux in liver and muscle fibers were assessed. We found that NR supplementation had no influence on body or organ weight, glucose metabolism or hepatic lipid accumulation, energy expenditure, or metabolic flexibility but increased mitochondrial respiration in soleus muscle in both mouse strains. Strain-dependent differences were detected for body and fat depot weight, fasting blood glucose, hepatic lipid accumulation, and energy expenditure. We conclude that, in mild obesity, NR supplementation does not alter metabolic phenotype in two commonly used laboratory mouse strains.

Chronic high-fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice.

Obesity is associated with dyslipidemia, ectopic lipid deposition, and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet (HFD)-induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high-fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient (Angptl4LivKO) mice, fed them a 60% kcal/fat diet (HFD) for 6 mo and assessed triglyceride, liver, and glucose metabolic phenotypes. We also explored the effects of prolonged fasting on Angptl4LivKO mice. The loss of hepatocyte-derived ANGPTL4 led to no major changes in triglyceride partitioning or lipoprotein lipase activity compared with control mice. Interestingly, although there was no difference in fasting plasma triglyceride levels after a 6 h fast, after an 18-h fast, normal chow diet-fed Angptl4LivKO mice had lower triglyceride levels than control mice. On a HFD, Angptl4LivKO mice initially showed no difference in glucose tolerance and insulin sensitivity, but improved glucose tolerance emerged in these mice after 6 mo on HFD. Our data suggest that hepatocyte ANGPTL4 does not directly regulate triglyceride partitioning, but that loss of liver-derived ANGPTL4 may be protective from HFD-induced glucose intolerance and influence plasma triglyceride (TG) metabolism during prolonged fasting.NEW & NOTEWORTHY1) Angiopoietin-like 4 deficiency in hepatocytes (Angptl4LivKO) does not improve triglyceride phenotypes during high-fat feeding. 2) Angptl4LivKO mice have improved glucose tolerance after chronic high-fat diet. 3) Angptl4LivKO mice have decreased fasting plasma triglyceride levels after an 18-h fast, but not after a 6-h fast.