Diet-induced Metabolic Dysfunction Research Articles

Brown adipose Vanin-1 is required for the maintenance of mitochondrial homeostasis and prevents diet-induced metabolic dysfunction

BackgroundEnergy-dissipating brown adipocytes have significant potential for improving systemic metabolism. Vanin-1, a membrane-bound pantetheinase, is involved in various biological processes in mice. However, its role in BAT mitochondrial function is still unclear. In this study, we aimed to elucidate the impact of Vanin-1 on BAT function and contribution during overnutrition-induced obesity. MethodsVanin-1 expression was analyzed in different adipose depots in mice. The cellular localization of Vanin-1 was analyzed by confocal microscopy and western blots. Mice lacking Vanin-1 (Vanin-1−/−) were continuously fed either a chow diet or a high-fat diet (HFD) to establish an obesity model. RNA-seq analysis was performed to identify the molecular changes associated with Vanin-1 deficiency during obesity. BAT-specific Vanin-1 overexpression mice were established to determine the effects of Vanin-1 in vivo. Cysteamine treatment was used to examine the effect of enzymatic reaction products of Vanin-1 on BAT mitochondria function in Vanin-1−/− mice. ResultsThe results indicate that the expression of Vanin-1 is reduced in BAT from both diet-induced and leptin-deficient obese mice. Study on the subcellular location of Vanin-1 shows that it has a mitochondrial localization. Vanin-1 deficiency results in increased adiposity, BAT dysfunction, aberrant mitochondrial structure, and promotes HFD induced-BAT whitening. This is attributed to the impairment of the electron transport chain (ETC) in mitochondria due to Vanin-1 deficiency, resulting in reduced mitochondrial respiration. Overexpression of Vanin-1 significantly enhances energy expenditure and thermogenesis in BAT, renders mice resistant to diet-induced obesity. Furthermore, treatment with cysteamine rescue the mitochondrial dysfunction in Vanin-1−/− mice. ConclusionsCollectively, these findings suggest that Vanin-1 plays a crucial role in promoting mitochondrial respiration to counteract diet-induced obesity, making it a potential therapeutic target for obesity.

17α-Estradiol alleviates high-fat diet-induced inflammatory and metabolic dysfunction in skeletal muscle of male and female mice.

17α-estradiol (17α-E2) is a naturally occurring nonfeminizing diastereomer of 17β-estradiol that has life span-extending effects in rodent models. To date, studies of the systemic and tissue-specific benefits of 17α-E2 have largely focused on the liver, brain, and white adipose tissue with far less focus on skeletal muscle. Skeletal muscle has an important role in metabolic and age-related disease. Therefore, this study aimed to determine whether 17α-E2 treatment has positive, tissue-specific effects on skeletal muscle during a high-fat feeding. We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during a high-fat diet (HFD) with changes in the mitochondrial proteome to support lipid oxidation and subsequent reductions in diacylglycerol (DAG) and ceramide content. To test this hypothesis, we used a multiomics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. Unexpectedly, we found that 17α-E2 had marked, but different, beneficial effects within each sex. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAG), and inflammatory cytokine levels, and altered the abundance of most of the proteins related to lipolysis and β-oxidation. Similar to male mice, 17α-E2 treatment reduced fat mass while protecting muscle mass in female mice but had little muscle inflammatory cytokine levels. Although female mice were resistant to HFD-induced changes in DAGs, 17α-E2 treatment induced the upregulation of six DAG species. In female mice, 17α-E2 treatment changed the relative abundance of proteins involved in lipolysis, β-oxidation, as well as structural and contractile proteins but to a smaller extent than male mice. These data demonstrate the metabolic benefits of 17α-E2 in skeletal muscle of male and female mice and contribute to the growing literature of the use of 17α-E2 for multi tissue health span benefits.NEW & NOTEWORTHY Using a multiomics approach, we show that 17α-E2 alleviates HFD-induced metabolic detriments in skeletal muscle by altering bioactive lipid intermediates, inflammatory cytokines, and the abundance of proteins related to lipolysis and muscle contraction. The positive effects of 17α-E2 in skeletal muscle occur in both sexes but differ in their outcome.

Treatment with a new barbituric acid derivative suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice

IntroductionNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, often accompanied by obesity, diabetes, and increased risks of depression and anxiety. Currently, there are no FDA-approved drugs to treat NAFLD and its related systemic symptoms. Previously, we identified a new barbituric acid derivative (BA-5) that expressed effectiveness against fibrosis and drug-resistant hepatocellular carcinoma. AimsThis study investigated the potential of BA-5 against high-fat diet (HFD)-induced NAFLD and mood disorders in mice. Main methodsSix-weeks-old male C57BL/6 mice were fed with a 45 % HFD for 8 weeks to induce NAFLD and associated metabolic disorders. Mice were treated with a BA-5 and the therapeutic effects and the underlying molecular mechanisms were investigated. Key findingsAdministration of BA-5 significantly reduced serum levels of alanine aminotransferase (ALT), low-density lipoprotein (LDL), fatty acids (FA), and triglycerides (TG) in HFD-fed mice. BA-5 treatment decreased expressions of hepatic lipogenesis-related markers (acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and ATP-citrate lyase (ACLY)), increased fatty acid oxidation markers (carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1)), and attenuated hepatic fat accumulation in HFD-fed mice. Moreover, HFD-induced adipocyte size enlargement and activation of lipolysis markers such as phosphorylated (p)-hormone-sensitive lipase (HSL) 565, p-HSL 660, and perilipin were inhibited in BA-5-treated mice. Notably, HFD-induced anxiety- and depression-like behaviors significantly improved in the BA-5 treated group through enhanced anti-inflammatory responses in the hippocampus. SignificanceThis study provides new insights into clinical therapeutic strategies of barbituric acid derivatives for HFD-induced NAFLD and associated mood disturbances.

Complementary yet divergent effects of exercise and an exercise mimetic on microbiome in high-fat diet-induced obesity.

Exercise is beneficial for obesity, partially through increased mitochondrial activity and raised nicotinamide adenine dinucleotide (NAD), a coenzyme critical for mitochondrial function and metabolism. Recent work has shown that increasing the availability of NAD through pharmacological means improves metabolic health in rodent models of diet-induced obesity and that the effect of these supplements when administered orally may be modulated by the gut microbiome. The gut microbiome is altered by both diet and exercise and is thought to contribute to some aspects of high-fat diet-induced metabolic dysfunction. We examined the independent and combined effects of treadmill exercise and nicotinamide mononucleotide (NMN) supplementation on the gut microbiome of female C57Bl6/J mice chronically fed a high-fat diet. We showed that 8 wk of treadmill exercise, oral-administered NMN, or combined therapy exert unique effects on gut microbiome composition without changing bacterial species richness. Exercise and NMN exerted additive effects on microbiota composition, and NMN partially or fully restored predicted microbial functions, specifically carbohydrate and lipid metabolism, to control levels. Further research is warranted to better understand the mechanisms underpinning the interactions between exercise and oral NAD+ precursor supplementation on gut microbiome.NEW & NOTEWORTHY Exercise and NAD+ precursor supplementation exerted additive and independent effects on gut microbiota composition and inferred function in female mice with diet-induced obesity. Notably, combining exercise and oral nicotinamide mononucleotide supplementation restored inferred microbial functions to control levels, indicating that this combination may improve high-fat diet-induced alterations to microbial metabolism.

Protective effect of probiotic Limosilactobacillus reuteri DSM17938 against western diet-induced obesity and associated metabolic alterations

PurposeTo evaluate the possible application of Limosilactobacillus reuteri DSM 17938 as a strategy to prevent Western Diet-induced metabolic alterations and liver dysfunction. MethodsMale Wistar rats of 90 days were divided in three groups and fed a control diet (CD), a high fat - high fructose diet alone (WD) or in combination with the administration of 108 CFU of L. reuteri (WD-R) for 8 weeks. Body composition, energy balance and plasma lipid profile were evaluated, together with hepatic glucose homeostasis and insulin sensitivity. Metabolic inflammation was also assessed at a whole-body level and in the liver, together with mitochondrial function and oxidative stress. ResultsRats that received the WD and L. reuteri administration exhibited a lower body lipid gain and a higher protein gain, underlying a beneficial effect of the probiotic in counteracting the development of obesity. Moreover, the WD-R rats were protected from the development of inflammation at a whole body and liver level and displayed normal glucose homeostasis and insulin sensitivity, a decreased hepatic lipid deposition and a preserved function of the mitochondrial respiratory chain and redox balance. ConclusionsWe demonstrate for the first time that Limosilactobacillus reuteri DSM 17938 has a strong efficacy in preventing the development of the hepatic metabolic derangement elicited by the Western diet administration. These are promising results that open the way for the use of this probiotic as a prevention strategy against the development of diet-related diseases, such as type two diabetes and metabolic syndrome.

The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue

Identifying molecular circuits that control adipose tissue macrophage (ATM) function is necessary to understand how ATMs contribute to tissue homeostasis and obesity-induced insulin resistance. In this study, we find that mice with a myeloid-specific knockout of the miR-23-27-24 clusters of microRNAs (miRNAs) gain less weight on a high-fat diet but exhibit worsened glucose and insulin tolerance. Analysis of ATMs from these mice shows selectively reduced numbers and proliferation of a recently reported subset of lipid-associated CD9+Trem2+ ATMs (lipid-associated macrophages [LAMs]). Leveraging the role of miRNAs to control networks of genes, we use RNA sequencing (RNA-seq), functional screens, and biochemical assays to identify candidate target transcripts that regulate proliferation-associated signaling. We determine that miR-23 directly targets the mRNA of Eif4ebp2, a gene that restricts protein synthesis and proliferation in macrophages. Altogether, our study demonstrates that control of proliferation of a protective subset of LAMs by noncoding RNAs contributes to protection against diet-induced obesity metabolic dysfunction.

Deficiency of Adipose Aryl Hydrocarbon Receptor Protects against Diet-Induced Metabolic Dysfunction through Sexually Dimorphic Mechanisms.

The molecular mechanisms underlying diet-induced obesity are complex and remain unclear. The activation of the aryl hydrocarbon receptor (AhR), a xenobiotic sensor, by obesogens may contribute to diet-induced obesity through influences on lipid metabolism and insulin resistance acting at various sites, including adipose tissue. Thus, our hypothesis was that conditional AhR depletion, specifically from mature adipose tissue (CadKO), would improve high-fat diet (HFD)-induced metabolic dysfunction. CadKO protects mice from HFD-induced weight gain. CadKO females eat fewer calories, leading to increased energy expenditure (EE) and improved glucose tolerance on HFD. Our exploration of adipose tissue biology suggests that the depletion of AhR from adipocytes provides female mice with an increased capacity for adipogenesis and lipolysis, allowing for the maintenance of a healthy adipocyte phenotype. The HFD-induced leptin rise was reduced in CadKO females, but the hypothalamic leptin receptor (LepR) was increased in the energy regulatory regions of the hypothalamus, suggesting an increased sensitivity to leptin. The estrogen receptor α (ERα) was higher in CadKO female adipose tissue and the hypothalamus. CadKO males displayed a delayed progression of obesity and insulin resistance. In males, CadKO ameliorated proinflammatory adipocytokine secretion (such as TNFα, IL1β, IL6) and displayed reduced inflammatory macrophage infiltration into adipose depots. Overall, CadKO improves weight control and systemic glucose homeostasis under HFD challenge but to a more profound extent in females. CadKO facilitates a lean phenotype in females and mediates healthy adipose-hypothalamic crosstalk. In males, adipose-specific AhR depletion delays the development of obesity and insulin resistance through the maintenance of healthy crosstalk between adipocytes and immune cells.

Preptin Deficiency Does Not Protect against High-Fat Diet-Induced Metabolic Dysfunction or Bone Loss in Mice.

Preptin is derived from the cleavage of the E-peptide of pro-insulin-like growth factor (IGF)-II and is an insulin secretagogue. Observational studies have linked elevated circulating preptin to metabolic dysfunction in humans; however, a causal role for preptin in metabolic dysfunction has not been established. Additionally, preptin can promote osteoblast proliferation and differentiation, suggesting a link with skeletal health. We previously described a global preptin knockout (KO) model. In this study, we sought to uncover the impact of preptin KO in mice on the response to a moderately high-fat diet (HFD) and low-fat diet (LFD). HFD groups had higher weight and fat mass gain, lower trabecular and cortical bone volume and fracture load, and higher liver triglycerides. In males, preptin deficiency led to lower blood glucose than wild-type (WT) mice under LFD conditions. This was accompanied by differences in bone microarchitecture, including lower trabecular bone volume fraction, trabecular number, and lower cortical thickness. These differences were absent in female mice, although KO females had a HFD-driven increase in fat mass and liver triglycerides that was absent in WT mice. Female WT mice had increased glucose-stimulated insulin secretion under HFD conditions that was absent in female KO mice. Overall, preptin may have a detrimental impact on metabolism and a positive impact on bone health in male mice and may protect against liver fat storage in females while enabling islet compensation under HFD conditions. When we consider that serum preptin levels are elevated in humans of both sexes in pathological states in which insulin levels are elevated, the impact of preptin on comorbidity risk needs to be better understood. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pharmacological antagonism of receptor for advanced glycation end products signaling promotes thermogenesis, healthful body mass and composition, and metabolism in mice.

Optimal body mass and composition as well as metabolic fitness require tightly regulated and interconnected mechanisms across tissues. Disturbances in these regulatory networks tip the balance between metabolic health versus overweight and obesity and their complications. The authors previously demonstrated roles for the receptor for advanced glycation end products (RAGE) in obesity, as global- or adipocyte-specific deletion of Ager (the gene encoding RAGE) protected mice from high-fat diet-induced obesity and metabolic dysfunction. To explore translational strategies evoked by these observations, a small molecule antagonist of RAGE signaling, RAGE229, was administered to lean mice and mice with obesity undergoing diet-induced weight loss. Body mass and composition and whole body and adipose tissue metabolism were examined. This study demonstrates that antagonism of RAGE signaling reduced body mass and adiposity and improved glucose, insulin, and lipid metabolism in lean male and female mice and in male mice with obesity undergoing weight loss. In adipose tissue and in human and mouse adipocytes, RAGE229 enhanced phosphorylation of protein kinase A substrates, which augmented lipolysis, mitochondrial function, and thermogenic programs. Pharmacological antagonism of RAGE signaling is a potent strategy to optimize healthful body mass and composition and metabolic fitness.

“Effect of time-restricted feeding on high-fat diet-induced metabolic dysfunction in Drosophila melanogaster”

BackgroundMetabolic alterations associated with obesity have been related to chronodisruption i.e., the desynchronization of molecular clocks that regulate circadian rhythms. The search for tools that improve the dietary treatment of obesity has recently focused on behaviors related to chronodisruption, and intermittent fasting is increasingly gaining interest. Studies in animal models have identified the benefits of time-restricted feeding (TRF) on metabolic alterations associated with changes in circadian rhythms induced by a high-fat diet. We aimed to evaluate the effect of TRF in flies with metabolic damage and chronodisruption. MethodsUsing high-fat diet fed Drosophila melanogaster as a model of metabolic damage and chronodisruption, we determined the impact of 12-h TRF on metabolic and molecular markers. Flies with metabolic dysfunction were switched to a control diet and randomly assigned to Ad libitum or a TRF regimen for seven days. We evaluated total triglyceride content, glycemia, weight, and 24 h mRNA expression rhythms of Nlaz (insulin resistance marker), clock genes (circadian rhythm molecular markers), and the neuropeptide Cch-amide2. ResultsFlies with metabolic damage that received TRF showed lower total triglyceride content, Nlaz expression, circulating glucose, and weight compared to Ad libitum. We observed the recovery of some of the high-fat diet-induced alterations in the amplitude of the circadian rhythm, particularly in the peripheral clock. ConclusionsTRF produced a partial reversal of metabolic dysfunction and chronodisruption of circadian cycles. General significanceTRF could be a useful tool to help to ameliorate metabolic and chronobiologic damage induced by a high-fat diet.

Intestinal α-Defensins Play a Minor Role in Modulating the Small Intestinal Microbiota Composition as Compared to Diet.

The intestinal microbiota is at the interface between the host and its environment and thus under constant exposure to host-derived and external modulators. While diet is considered to be an important external factor modulating microbiota composition, intestinal defensins, one of the major classes of antimicrobial peptides, have been described as key host effectors that shape the gut microbial community. However, since dietary compounds can affect defensin expression, thereby indirectly modulating the intestinal microbiota, their individual contribution to shaping gut microbiota composition remains to be defined. To disentangle the complex interaction among diet, defensins, and small-intestinal microbiota, we fed wild-type (WT) mice and mice lacking functionally active α-defensins (Mmp7-/- mice) either a control diet or a Western-style diet (WSD) that is rich in saturated fat and simple carbohydrates but low in dietary fiber. 16S rDNA sequencing and robust statistical analyses identified that bacterial composition was strongly affected by diet while defensins had only a minor impact. These findings were independent of sample location, with consistent results between the lumen and mucosa of the jejunum and ileum, in both mouse genotypes. However, distinct microbial taxa were also modulated by α-defensins, which was supported by differential antimicrobial activity of ileal protein extracts. As the combination of WSD and defensin deficiency exacerbated glucose metabolism, we conclude that defensins only have a fine-tuning role in shaping the small-intestinal bacterial composition and might instead be important in protecting the host against the development of diet-induced metabolic dysfunction. IMPORTANCE Alterations in the gut microbial community composition are associated with many diseases, and therefore identifying factors that shape the microbial community under homeostatic and diseased conditions may contribute to the development of strategies to correct a dysbiotic microbiota. Here, we demonstrate that a Western-style diet, as an extrinsic parameter, had a stronger impact on shaping the small intestinal bacterial composition than intestinal defensins, as an intrinsic parameter. While defensins have been previously shown to modulate bacterial composition in young mice, our study supplements these findings by showing that defensins may be less important in adult mice that harbor a mature microbial community. Nevertheless, we observed that defensins did affect the abundance of distinct bacterial taxa in adult mice and protected the host from aggravated diet-induced glucose impairments. Consequently, our study uncovers a new angle on the role of intestinal defensins in the development of metabolic diseases in adult mice.

Bioactive Compounds as Inhibitors of Inflammation, Oxidative Stress and Metabolic Dysfunctions via Regulation of Cellular Redox Balance and Histone Acetylation State.

Bioactive compounds (BCs) are known to exhibit antioxidant, anti-inflammatory, and anti-cancer properties by regulating the cellular redox balance and histone acetylation state. BCs can control chronic oxidative states caused by dietary stress, i.e., alcohol, high-fat, or high-glycemic diet, and adjust the redox balance to recover physiological conditions. Unique functions of BCs to scavenge reactive oxygen species (ROS) can resolve the redox imbalance due to the excessive generation of ROS. The ability of BCs to regulate the histone acetylation state contributes to the activation of transcription factors involved in immunity and metabolism against dietary stress. The protective properties of BCs are mainly ascribed to the roles of sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (NRF2). As a histone deacetylase (HDAC), SIRT1 modulates the cellular redox balance and histone acetylation state by mediating ROS generation, regulating nicotinamide adenine dinucleotide (NAD+)/NADH ratio, and activating NRF2 in metabolic progression. In this study, the unique functions of BCs against diet-induced inflammation, oxidative stress, and metabolic dysfunction have been considered by focusing on the cellular redox balance and histone acetylation state. This work may provide evidence for the development of effective therapeutic agents from BCs.

High-fat/high-sucrose diet worsens metabolic outcomes and widespread hypersensitivity following early-life stress exposure in female mice.

Exposure to stress early in life has been associated with adult-onset comorbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early-life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early-life stress and consumption of a Western-style diet contribute to the development of obesity; however, relatively few preclinical studies have been performed in female rodents, which are known to be protected against diet-induced obesity and metabolic dysfunction. In this study, we gave naïve and NMS female mice access to a high-fat/high-sucrose (HFS) diet beginning at 4 wk of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 wk on the diet, driven partly by increased food intake. Female NMS mice on an HFS diet showed widespread mechanical hypersensitivity compared with either naïve mice on an HFS diet or NMS mice on a control diet. HFS diet-fed NMS mice also had impaired glucose tolerance and fasting hyperinsulinemia. Strikingly, female NMS mice on an HFS diet showed evidence of hepatic steatosis with increased triglyceride levels and altered glucocorticoid receptor levels and phosphorylation state. They also exhibited increased energy expenditure as observed via indirect calorimetry and expression of proinflammatory markers in perigonadal adipose. Altogether, our data suggest that early-life stress exposure increased the susceptibility of female mice to develop diet-induced metabolic dysfunction and pain-like behaviors.

Promotion of diet-induced obesity and metabolic syndromes by BID is associated with gut microbiota.

A growing body of evidence has indicated an expanding functional network of B-cell lymphoma 2 (BCL-2) family proteins beyond regulation of cell death and survival. Here, we examined the role and mechanisms of BH3 interacting-domain death agonist (BID), a pro-death BCL-2 family member, in the development of diet-induced metabolic dysfunction. Mice deficient in bid (bid-/- ) were resistant to high-fat diet (HFD)-induced obesity, hepatic steatosis, and dyslipidemia with an increased insulin sensitivity. Indirect calorimetry analysis indicated that bid deficiency increased metabolic rate and decreased respiratory exchange ratio, suggesting a larger contribution of lipids to overall energy expenditure. While expression of several genes related to lipid accumulation was only increased in wild-type livers, metabolomics analysis revealed a consistent reduction in fatty acids but an increase in certain sugars and Krebs cycle intermediates in bid-/- livers. Gut microbiota (GM) analysis indicated that HFD induced gut dysbiosis with differential patterns in wild-type and in bid-/- mice. Notably, abrogation of GM by antibiotics during HFD feeding eliminated the beneficial effects against obesity and hepatic steatosis conferred by the bid deficiency. Conclusion: These results indicate that the protective role of bid-deficiency against diet-induced metabolic dysfunction interacts with the function of GM.

Mechanism(s) for age-related sex differences in diet-induced cardiomyopathy: role of RNA methylation

Abstract Background/Introduction Age and sexual dimorphism contribute to the differential cardiometabolic dysfunctions associated with diet-induced obesity. However, the underlying mechanisms remain elusive. RNA modifications via RNA m6A methylation, is an emerging mediator of RNA stability, translation and localization responsible for regulation of multiple biological functions. RNA m6A modifications are regulated by “writers”, “erasers” and “readers”. The role of RNA methylation machinery genes in the heart is largely unexplored, and may provide insight into the influence of age and sex on cardiometabolic dysfunction. Purpose We aim to determine differential RNA methylation changes within the heart in a diet-induced cardiomyopathy mouse model, stratified according to age and sex. Methods Male and female C57BL/6 mice (6–8wk-old) were fed normal chow (NC) or high-fat/high-sucrose (HFHS) diet for 1 or 4 months. Echocardiographic measurements were performed at 1 and 4 months according to the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines. At study endpoint, glucose and insulin tolerance testing was conducted by injecting mice intraperitoneally with 2g/kg glucose or 0.6U/kg insulin, and monitoring blood glucose levels over a 2 hour period. RNA from heart tissue was subjected to quantitative PCR for RNA methylation machinery genes (FTO, ALKBH5, METTL3, METTL4, METTL14, YTHDF1 and YTHDF2). PPIA was used to normalise qPCR data. Results Both male and female mice showed evidence of age- and diet-induced metabolic dysfunction, however, males and females showed markedly different metabolic impairments. For example, glucose tolerance was exacerbated by 4 months of HFHS diet in males but not females; and only females showed impaired insulin tolerance. Echocardiography showed that males had systolic (stoke volume, cardiac output) and diastolic (E/A ratio) dysfunction after 4 months of HFHS diet, while females were unperturbed. We identified that METTL3 and METTL14, the “writers” of m6A methylation, were consistently increased in male mouse hearts at 1 vs 4 months of age but were unchanged or decreased in females, irrespective of diet. Conversely, YTHDF1, a “reader”, was unchanged in male mouse hearts at 1 vs. 4 months of age but was significantly increased in female hearts. Conclusion Our study confirms that markedly different cardiometabolic impairments occur in male versus female mice in response to long-term HFHS diet. Despite significant metabolic impairment in both sexes, cardiac dysfunction was only evident in males. RNA methylation machinery genes were differentially expressed in mouse hearts according to age and sex, suggesting that RNA methylation may be involved in age-related sexual dimorphism in cardiometabolic impairments. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Heart Foundation

Sex-Dependent Role of Adipose Tissue HDAC9 in Diet-Induced Obesity and Metabolic Dysfunction.

Obesity is a major risk factor for both metabolic and cardiovascular disease. We reported that, in obese male mice, histone deacetylase 9 (HDAC9) is upregulated in adipose tissues, and global deletion of HDAC9 protected against high fat diet (HFD)-induced obesity and metabolic disease. Here, we investigated the impact of adipocyte-specific HDAC9 gene deletion on diet-induced obesity in male and female mice. The HDAC9 gene expression was increased in adipose tissues of obese male and female mice and HDAC9 expression correlated positively with body mass index in humans. Interestingly, female, but not male, adipocyte-specific HDAC9 KO mice on HFD exhibited reduced body weight and visceral adipose tissue mass, adipocyte hypertrophy, and improved insulin sensitivity, glucose tolerance and adipogenic differentiation gene expression. Furthermore, adipocyte-specific HDAC9 gene deletion in female mice improved metabolic health as assessed by whole body energy expenditure, oxygen consumption, and adaptive thermogenesis. Mechanistically, compared to female mice, HFD-fed male mice exhibited preferential HDAC9 expression in the stromovascular fraction, which may have offset the impact of adipocyte-specific HDAC9 gene deletion in male mice. These results suggest that HDAC9 expressed in adipocytes is detrimental to obesity in female mice and provides novel evidence of sex-related differences in HDAC9 cellular expression and contribution to obesity-related metabolic disease.

Vitamin C attenuates predisposition to high-fat diet-induced metabolic dysregulation in GLUT10-deficient mouse model

BackgroundThe development of type 2 diabetes mellitus (T2DM) is highly influenced by complex interactions between genetic and environmental (dietary and lifestyle) factors. While vitamin C (ascorbic acid, AA) has been suggested as a complementary nutritional treatment for T2DM, evidence for the significance and beneficial effects of AA in T2DM is thus far inconclusive. We suspect that clinical studies on the topic might need to account for combination of genetic and dietary factors that could influence AA effects on metabolism. In this study, we tested this general idea using a mouse model with genetic predisposition to diet-induced metabolic dysfunction. In particular, we utilized mice carrying a human orthologous GLUT10G128E variant (GLUT10G128E mice), which are highly sensitive to high-fat diet (HFD)-induced metabolic dysregulation. The genetic variant has high relevance to human populations, as genetic polymorphisms in glucose transporter 10 (GLUT10) are associated with a T2DM intermediate phenotype in nondiabetic population.ResultsWe investigated the impacts of AA supplementation on metabolism in wild-type (WT) mice and GLUT10G128E mice fed with a normal diet or HFD. Overall, the beneficial effects of AA on metabolism were greater in HFD-fed GLUT10G128E mice than in HFD-fed WT mice. At early postnatal stages, AA improved the development of compromised epididymal white adipose tissue (eWAT) in GLUT10G128E mice. In adult animals, AA supplementation attenuated the predisposition of GLUT10G128E mice to HFD-triggered eWAT inflammation, adipokine dysregulation, ectopic fatty acid accumulation, metabolic dysregulation, and body weight gain, as compared with WT mice.ConclusionsTaken together, our findings suggest that AA has greater beneficial effects on metabolism in HFD-fed GLUT10G128E mice than HFD-fed WT mice. As such, AA plays an important role in supporting eWAT development and attenuating HFD-induced metabolic dysregulation in GLUT10G128E mice. Our results suggest that proper WAT development is essential for metabolic regulation later in life. Furthermore, when considering the usage of AA as a complementary nutrition for prevention and treatment of T2DM, individual differences in genetics and dietary patterns should be taken into account.

BAF60a Deficiency in Macrophage Promotes Diet-Induced Obesity and Metabolic Inflammation.

Adipose tissue macrophage (ATM) has been shown to play a key role in the pathogenesis of obesity-associated adipose tissue inflammation and metabolic diseases. However, the upstream factors that integrate the environmental signals to control ATM activation and adipose inflammation in obesity remain elusive. Here, we identify BAF60a, a subunit of the switch/sucrose-nonfermentable (SWI/SNF) chromatin remodeling complexes, as the central checkpoint regulator of obesity-induced ATM activation, adipose tissue inflammation, and systemic metabolic impairment. BAF60a expression was robustly downregulated in the adipose tissue stromal vascular fractions in type 2 diabetic mice. Myeloid-specific BAF60a knockout (BaMKO) promotes ATM proinflammatory activation, exacerbating diet-induced obesity, insulin resistance, and metabolic dysfunction. Conversely, myeloid-specific overexpression of BAF60a in mice attenuates macrophage proinflammatory activation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that BAF60a inactivation triggers the expression of proinflammatory gene program through chromatin remodeling. Moreover, motif analysis of ATAC-Seq and CUT&Tag-Seq data identifies the transcription factor Atf3 that physically interacts with BAF60a to suppress the proinflammatory gene expression, thereby controlling ATM activation and metabolic inflammation in obesity. Consistently, myeloid-specific Atf3 deficiency also promotes the proinflammatory activation of macrophage. This work uncovers BAF60a/Atf3 axis as the key regulator in obesity-associated ATM activation, adipose tissue inflammation, and metabolic diseases.

Black Tea Reduces Diet-Induced Obesity in Mice via Modulation of Gut Microbiota and Gene Expression in Host Tissues.

Black tea was reported to alter the microbiome populations and metabolites in diet-induced obese mice and displays properties that prevent obesity, but the underlying mechanism of the preventative effect of black tea on high-fat diet (HFD) induced obesity has not been elucidated. Epigenetic studies are a useful tool for determining the relationship between obesity and environment. Here, we show that the water extract of black tea (Lapsang souchong, LS) reverses HFD-induced gut dysbiosis, alters the tissue gene expression, changes the level of a major epigenetic modification (DNA methylation), and prevents obesity in HFD feeding mice. The anti-obesity properties of black tea are due to alkaloids, which are the principal active components. Our data indicate that the anti-obesity benefits of black tea are transmitted via fecal transplantation, and the change of tissue gene expression and the preventative effects on HFD-induced obesity in mice of black tea are dependent on the gut microbiota. We further show that black tea could regulate the DNA methylation of imprinted genes in the spermatozoa of high-fat diet mice. Our results show a mechanistic link between black tea, changes in the gut microbiota, epigenetic processes, and tissue gene expression in the modulation of diet-induced metabolic dysfunction.

Diet-Induced Metabolic Dysfunction of Hypothalamic Nutrient Sensing in Rodents.

A sedentary lifestyle and excessive nutrient intake resulting from the consumption of high-fat and calorie-rich diets are environmental factors contributing to the rapid growth of the current pandemic of type 2 diabetes mellitus (DM2). Fasting hyperglycemia, an established hallmark of DM2, is caused by excessive production of glucose by the liver, resulting in the inability of insulin to suppress endogenous glucose production. To prevent inappropriate elevations of circulating glucose resulting from changes in nutrient availability, mammals rely on complex mechanisms for continuously detecting these changes and to respond to them with metabolic adaptations designed to modulate glucose output. The mediobasal hypothalamus (MBH) is the key center where nutritional cues are detected and appropriate modulatory responses are integrated. However, certain environmental factors may have a negative impact on these adaptive responses. For example, consumption of a diet enriched in saturated fat in rodents resulted in the development of a metabolic defect that attenuated these nutrient sensing mechanisms, rendering the animals prone to developing hyperglycemia. Thus, high-fat feeding leads to a state of “metabolic disability” in which animals’ glucoregulatory responses fail. We postulate that the chronic faltering of the hypothalamic glucoregulatory mechanisms contributes to the development of metabolic disease.