Western Diet-induced Obesity Research Articles

Western diet promotes the progression of metabolic dysfunction-associated steatotic liver disease in association with ferroptosis in male mice.

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is a silent killer that often progresses to metabolic dysfunction-associated steatohepatitis (MASH). To date, there are no pharmacological treatments for MASLD. While obesity is a major cause of the development and progression of MASLD, the underlying mechanisms remain unclear. We hypothesize that ferroptosis, a recently discovered nonapoptotic iron-dependent form of cell death, is activated during the progression of MASLD and may be a potential target for treating MASLD. Using a murine model of Western diet-induced obesity, C57BL/6J male mice were exposed to a long-term (36 weeks) Western diet. Controls were maintained with a standard chow diet. Western diet-induced obesity was confirmed by increased body mass index (BMI). Histopathological analysis demonstrated the progression of MASLD to MASH in the obese group, which was accompanied by significant hepatic iron deposition, oxidative damage, and lipid peroxidation. Hepatic ferroptosis was further confirmed by decreased protein expression of glutathione peroxidase 4 (GPX4) and increased acyl-CoA synthetase long-chain family member 4 (ACSL4), markers of ferroptosis. These findings suggest that ferroptosis is a potential mechanism involved in the pathogenesis of MASLD in male mice.

Paternal obesity induces changes in sperm chromatin accessibility and has a mild effect on offspring metabolic health

The increasing global burden of metabolic disorders including obesity and diabetes necessitates a comprehensive understanding of their etiology, which not only encompasses genetic and environmental factors but also parental influence. Recent evidence has unveiled paternal obesity as a contributing factor to offspring's metabolic health via sperm epigenetic modifications. In this study, we investigated the impact of a Western diet-induced obesity in C57BL/6 male mice on sperm chromatin accessibility and the subsequent metabolic health of their progeny. Utilizing Assay for Transposase-Accessible Chromatin with sequencing, we discovered 450 regions with differential accessibility in sperm from obese fathers, implicating key developmental and metabolic pathways. Contrary to expectations, these epigenetic alterations in sperm were not predictive of long-term metabolic disorders in offspring, who exhibited only mild transient metabolic changes early in life. Both male and female F1 progeny showed no enduring predisposition to obesity or diabetes. These results underscore the biological resilience of offspring to paternal epigenetic inheritance, suggesting a complex interplay between inherited epigenetic modifications and the offspring's own developmental compensatory mechanisms. This study calls for further research into the biological processes that confer this resilience, which could inform interventional strategies to combat the heritability of metabolic diseases.

Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

Western diet-induced obesity results in brain mitochondrial dysfunction in female Ossabaw swine.

Diet-induced obesity is implicated in the development of a variety of neurodegenerative disorders. Concurrently, the loss of mitochondrial Complex I protein or function is emerging as a key phenotype across an array of neurodegenerative disorders. Therefore, the objective of this study was to determine if Western diet (WD) feeding in swine [carbohydrate = 40.8% kCal (17.8% of total calories from high fructose corn syrup), protein = 16.2% kcal, fat = 42.9% kCal, and 2% cholesterol] would result in Complex I syndrome pathology. To characterize the effects of WD-induced obesity on brain mitochondria in swine, high resolution respirometry measurements from isolated brain mitochondria, oxidative phosphorylation Complex expression, and indices of oxidative stress and mitochondrial biogenesis were assessed in female Ossabaw swine fed a WD for 6-months. In line with Complex I syndrome, WD feeding severely reduced State 3 Complex I, State 3 Complex I and II, and uncoupled mitochondrial respiration in the hippocampus and prefrontal cortex (PFC). State 3 Complex I mitochondrial respiration in the PFC inversely correlated with serum total cholesterol. WD feeding also significantly reduced protein expression of oxidative phosphorylation Complexes I-V in the PFC. WD feeding significantly increased markers of antioxidant defense and mitochondrial biogenesis in the hippocampi and PFC. These data suggest WD-induced obesity may contribute to Complex I syndrome pathology by increasing oxidative stress, decreasing oxidative phosphorylation Complex protein expression, and reducing brain mitochondrial respiration. Furthermore, these findings provide mechanistic insight into the clinical link between obesity and mitochondrial Complex I related neurodegenerative disorders.

Effects of Sulforaphane and Chlorophyl a in a Western Diet-Induced Obesity Model

The global rise in obesity and its co-morbidities raises worldwide health, social and economic concerns, especially in developed countries. Compounds derived from natural sources are now in the focus of pharmacological therapies. In recent years, sulforaphane (SFN) has been the subject of studies due to its anti-cancer, anti-inflammatory, antioxidant and potential anti-obesity effects. Lately, some studies have also reported the anti-obesogenic potential of chlorophyll. In this study, we evaluated the anti-obesity effects of SFN and chlorophyll a (Chlo.a) in C57BL/6J mice fed with a Western diet, rich in sugar and fat. The study lasted 14 weeks, and for the last 4 weeks SFN (0.25 or 0.5 mg/kg/day) or Chlo.a (0.2 or 0.5 mg/kg/day) was administered orally. The results showed that supplementation with SFN or Chlo.a resulted in an increase in body temperature and a reduction in the size of adipocytes. However, the administration of SFN or Chlo.a for 4 weeks did not decrease the body weight gain or hepatic steatosis, and increased hepatic ROS counterbalancing with an increase in SOD activity. In conclusion, in the animal model used, treatment with SFN or Chlo.a did not show strong anti-obesity effects; however, slight improvements were observed with the supplementation of these compounds.

Insulin-like growth factor-1 short-period therapy improves Non-Alcoholic Fatty Liver Disease (NAFLD) in obese mice

This study seeks to evaluate Insulin-like Growth Factor 1 (IGF-1) short-period therapy in Non-Alcoholic Fatty Liver Disease (NAFLD) as it relates to western diet-induced obesity. For this purpose, 21-day-old male Swiss mice were divided into a control group (CG, N=8), which was fed a standard diet, and an obese group (GO, N=16), which was fed a western diet, rich in saturated fat and simple carbohydrates, for 12 weeks. In the 11th week, part of the animals in the obese group (N=8) received a daily subcutaneous injection of recombinant human IGF-1 (100µg/kg/day) during seven consecutive days (GO+IGF-1). Biometric and metabolic parameters, intraperitoneal glucose tolerance test (IGTT), quantitative analysis of liver steatosis, quantitative analysis of collagen in liver and expression of immunoperoxidase of alpha-smooth muscle actin (a-SMA) were analyzed. Our data demonstrated that IGF-1 short-term treatment was able to improve obesity-related biometric and metabolic parameters. In addition, it promoted the recovery of liver parenchyma, thereby reducing steatosis and fibrosis, thus demonstrating an important hepatoprotective action.

Comparison of western diet-induced obesity and streptozotocin mouse models: insights into energy balance, somatosensory dysfunction, and cardiac autonomic neuropathy.

Metabolic disorders such as obesity and type 2 diabetes (T2D) are increasingly prevalent worldwide, necessitating a deeper comprehension of their underlying mechanisms. However, translating findings from animal research to human patients remains challenging. This study aimed to investigate the long-term effects of Streptozotocin (STZ) on metabolic, cardiac, and somatosensory function in mice fed a Western diet (WD) of high fat, sucrose, and cholesterol with low doses of STZ administration compared to mice fed WD alone. In our research, we thoroughly characterized energy balance and glucose homeostasis, as well as allodynia and cardiac function, all of which have been previously shown to be altered by WD feeding. Notably, our findings revealed that the treatment of WD-fed mice with STZ exacerbated dysfunction in glucose homeostasis via reduced insulin secretion in addition to impaired peripheral insulin signaling. Furthermore, both WD and WD + STZ mice exhibited the same degree of cardiac autonomic neuropathy, such as reduced heart rate variability and decreased protein levels of cardiac autonomic markers. Furthermore, both groups developed the same symptoms of neuropathic pain, accompanied by elevated levels of activating transcription factor 3 (Atf3) in the dorsal root ganglia. These discoveries enhance our understanding of metabolic activity, insulin resistance, neuropathy, and cardiac dysfunction of diet-induced models of obesity and diabetes. The exacerbation of impaired insulin signaling pathways by STZ did not lead to or worsen cardiac and somatosensory dysfunction. Additionally, they offer valuable insights into suitable diet induced translational mouse models, thereby advancing the development of potential interventions for associated conditions.

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.

Pterostilbene Enhances Thermogenesis and Mitochondrial Biogenesis by Activating the SIRT1/PGC-1α/SIRT3 Pathway to Prevent Western Diet-Induced Obesity.

Sirtuin 1/peroxisome proliferator-activated receptor gamma co-activator 1 alpha (SIRT1/PGC-1α) pathway activation is known to promote thermogenesis and mitochondrial biogenesis. Pterostilbene (PSB) and pinostilbene (PIN), the methylated analogs of resveratrol, are potential candidates to enhance thermogenesis and mitochondrial biogenesis. A model of Western diet-induced obesity in mice is designed. Either PSB or PIN is supplemented in the diet for 16 weeks. Both samples can significantly reduce body weight gain but only PSB can decrease inguinal adipose tissue weight. Besides, both samples can promote lipolysis but only PSB supplementation activates the SIRT1/PGC-1α/SIRT3 pathway to enhance mitochondrial biogenesis and thermogenesis in the inguinal adipose tissue. In addition, although both samples exert a modulatory effect on gut microbiota but significant increments in fecal isobutyric acid, valeric acid, and isovaleric acid are only observed in the PSB group, functioning as gut microbial metabolites. Overall, these findings suggest PSB and PIN as potential candidates for the improvement of obesity and gut microbiota dysbiosis. With its higher stability, PSB exerts a greater effect than PIN by promoting thermogenesis and mitochondrial biogenesis via SIRT1 activation.

The Role of Interferon Receptors α/β/γ Ablation During Western Diet-Induced Obesity and Insulin Resistance in the Inflectional Model AG129 Mice Strain.

Diet-induced obesity triggers elevation of circulating pro-inflammatory cytokines and acute-phase proteins, including interferons (IFNs). IFNs strongly contribute to low-grade inflammation associated with obesity-related complications, such as nonalcoholic fat liver disease and diabetes. In this study, AG129 mice model (double-knockout strain for IFN α/β/γ receptors) was fed with a high-fat high-sucrose (HFHS) diet (Western diet) for 20 weeks aiming to understand the impact of IFN receptor ablation on diet-induced obesity, insulin resistance, and nonalcoholic fat liver disease. Mice were responsive to the diet, becoming obese after 20 weeks of HFHS diet which was accompanied by 2-fold increase of white adipose tissues. Moreover, animals developed glucose and insulin intolerance, as well as dysregulation of insulin signaling mediators such as Insulin Receptor Substrate 1 (IRS1), protein kinase B (AKT), and S6 ribosomal protein. Liver increased interstitial cells, and lipid accumulation was also found, presenting augmented fibrotic markers (transforming growth factor beta 1 [Tgfb1], Keratin 18 [Krt18], Vimentin [Vim]), yet lower expression on IFN receptor downstream proteins (Toll-like receptor [TLR] 4, nuclear factor kappa-light-chain-enhancer of activated B cells [NFκB], and cAMP response element-binding protein [CREB]). Thus, IFN receptor ablation promoted effects on NFκB and CREB pathways, with no positive effects on systemic homeostasis in diet-induced obese mice. Therefore, we conclude that IFN receptor signaling is not essential for promoting the complications of diet-induced obesity and thus cannot be correlated with metabolic diseases in a noninfectious condition.

Western diet-induced obesity interferes with the HPA axis-blunting effects of palatable food in male rats

Limited intermittent consumption of palatable food reduces HPA axis responses to stress in chow-fed rats, and this effect is dependent on the rewarding properties of the palatable food. However, obesity may be a state of reduced consummatory food reward, suggesting that palatable foods may be less effective at blunting HPA axis reactivity in the context of diet-induced obesity (DIO). To test this hypothesis, adult male Long-Evans rats were given unlimited access to Western (high-fat, high-sugar) diet (WD) vs. normal chow (controls). After 8 weeks of diet exposure, rats were given limited sucrose intake (LSI) consisting of additional twice-daily access to a small amount (4 ml) of either 3% or 30% sucrose drink, or water (controls) for 2 weeks. Rats then received an acute restraint stress challenge, with collection of tail blood samples for measurement of plasma corticosterone. WD-fed rats had increased caloric intake, body weight and adiposity, as expected. Rats offered LSI (3% or 30%) readily drank the maximal amount allowed (8 ml/day) and reduced their dietary intake to compensate for the sucrose calories, such that LSI did not alter body weight regardless of diet type. In chow-fed lean rats, LSI with either 3% or 30% sucrose reduced the plasma corticosterone response to restraint stress, but this effect was absent in WD-fed DIO rats. Together, these data support the hypothesis that obesity attenuates stress blunting by palatable foods and suggest the possibility that consequently, individuals with obesity may need to consume larger amounts of palatable food to obtain adequate stress relief.

Brassica rapa L. prevents Western diet-induced obesity in C57BL/6 mice through its binding capacity of cholesterol and fat.

Obesity, a chronic disorder caused by excessive energy intake leading to fat accumulation in adipose tissue, increases the risk of severe diseases. Brassica rapa L. is known as a traditional vegetable in the Nagano area of Japan. C57BL/6 mice were randomly assigned to three groups, with different diets as follows: a normal diet, a Western diet (WD), and a WD plus B. rapa L. powder (BP) in a 56-day experiment. Brassica rapa L. supplementation reduced the body weight gain and lipid accumulation of mice significantly. The BP group also had higher fecal bile acid, total cholesterol, and triglyceride excretion levels compared with those in the other groups. The antiobesity effects of B. rapa L. were due to its binding with cholesterol and fat, and possibly enhancing the bile acid excretion and modulating gut microbiota, suggesting thatB. rapaL. could be a functional vegetable with potential uses in targeting obesity.

Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis-A Narrative Review.

The present study aims to provide a narrative review of the molecular mechanisms of Western diet-induced obesity and obesity-related carcinogenesis. A literature search of the Cochrane Library, Embase and Pubmed databases, Google Scholar and the grey literature was conducted. Most of the molecular mechanisms that induce obesity are also involved in the twelve Hallmarks of Cancer, with the fundamental process being the consumption of a highly processed, energy-dense diet and the deposition of fat in white adipose tissue and the liver. The generation of crown-like structures, with macrophages surrounding senescent or necrotic adipocytes or hepatocytes, leads to a perpetual state of chronic inflammation, oxidative stress, hyperinsulinaemia, aromatase activity, activation of oncogenic pathways and loss of normal homeostasis. Metabolic reprogramming, epithelial mesenchymal transition, HIF-1α signalling, angiogenesis and loss of normal host immune-surveillance are particularly important. Obesity-associated carcinogenesis is closely related to metabolic syndrome, hypoxia, visceral adipose tissue dysfunction, oestrogen synthesis and detrimental cytokine, adipokine and exosomal miRNA release. This is particularly important in the pathogenesis of oestrogen-sensitive cancers, including breast, endometrial, ovarian and thyroid cancer, but also 'non-hormonal' obesity-associated cancers such as cardio-oesophageal, colorectal, renal, pancreatic, gallbladder and hepatocellular adenocarcinoma. Effective weight loss interventions may improve the future incidence of overall and obesity-associated cancer.

Caspase-2 in liver disease and hepatocellular carcinoma

Caspases are key factors in the regulation of the apoptotic and/or inflammatory responses, both crucial in the pathogenesis of diverse diseases. Caspase-2 is the most evolutionary conserved albeit functionally poorly defined member of the caspase family. The precise role of caspase-2 as an initiator or effector caspase is still unknown, but it has been involved in a wide variety of functions, from apoptosis to genomic stability, oxidative stress, metabolism, and cancer. However, many conflicting results render the exact function of this protease still unresolved. Although caspase-2 has several hundred substrates, the activation, processing, and activity on specific substrates remain poorly described. Recent evidence indicates that caspase-2 has a role in metabolic homeostasis and is required for lipotoxicity-induced apoptosis in hepatocytes, contributing to non-alcoholic steatohepatitis (NASH) progression towards hepatocellular carcinoma (HCC). Caspase-2 protein expression strongly localizes to injured/ballooned hepatocytes, correlating with NASH severity. Also, mice lacking caspase-2 showed protection from western diet-induced obesity, dyslipidemia, and insulin resistance. Although there are no effective therapies for NASH and HCC, the evaluation of a pan-caspase inhibitor has reached a phase I/II in clinical trials for advanced liver disease. Nevertheless, a better understanding of caspase functions with the identification of specific proteolytic substrates is essential for future therapeutic developments. Bearing in mind the pressing need to identify new targets for NASH-HCC and its metabolic-related comorbidities, and the favorable effect of caspase-2 genetic inhibition in animal models, pharmacological caspase-2 inhibition arises as a promising strategy that should be further investigated.

Retraction Note: The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities

Retraction Note: The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities

Pharmacological Inhibition of Cullin Neddylation Improves Hepatic Insulin Sensitivity

Background and significanceHepatic insulin resistance is a hallmark feature of non‐alcoholic fatty liver disease (NAFLD) and type‐2 diabetes (T2D) and significantly contributes to systemic insulin resistance. Abnormal activation of nutrient and stress‐sensing kinases leads to serine/threonine phosphorylation of insulin receptor substrate (IRS) and subsequent IRS proteasome degradation, which is a key underlying cause of hepatic insulin resistance. Recently, members of the cullin‐RING E3 ligases (CRLs) have emerged as mediators of IRS protein turnover. CRLs are activated upon cullin neddylation, a process of covalent conjugation of a ubiquitin‐like protein called Nedd8 to a cullin scaffold.AimTo investigate the role of CRLs in regulating hepatic insulin signaling in NAFLD.MethodsNeddylation inhibitor MLN4924 was used to study its effect on insulin sensitivity in liver cells. Hyperinsulinemic‐euglycemic clamp was used to assess MNL4924 effect on insulin sensitivity in vivo. siRNA‐mediated screening was used to identify the Cullin members that mediates IRS protein turnover in liver cells. Co‐immunoprecipitation was performed to study Cullin and IRS interaction. Glucose homeostasis and insulin sensitivity were studied in mice with AAV‐mediated liver specific knockdown of Cul1 or Cul3.ResultsNeddylation inhibition delays CRL‐mediated IRS protein turnover to prolong insulin action in cultured liver cells. Consistently, acute MLN4924 treatment rapidly decreases hepatic glucose production without causing hypoglycemia in mice, while chronic MLN4924 treatment completely normalizes hyperglycemia in obese mice independent of obesity. Hyperinsulinemic‐euglycemic clamp study revealed that MLN4924 significantly increased insulin sensitivity and improved hepatic glucose output. In vitro siRNA based screening showed that knockdown of Cul1 or Cul3, but not other cullin family members, stabilized IRS protein and increased insulin sensitivity in AML12 cells. Consistently, Co‐immunoprecipitation demonstrated IRS interaction with Cul1 and Cul3. AAV‐mediated liver specific knockdown of Cul1 in mice improved insulin sensitivity, lowered fasting glucose, and prevented Western diet‐induced obesity and NAFLD. In contrast, AAV‐mediated liver Cul3 knockdown only decreased fasting glucose in chow‐fed mice but not Western diet‐fed mice.ConclusionThese findings suggest that pharmacological inhibition of cullin neddylation is a novel therapeutic strategy for hepatic insulin sensitization in NAFLD and T2D. This effect may be at least in part mediated by hepatic Cul1 and Cul3 neddylation.

Lymphatic Valve Dysfunction in Western Diet-Fed Mice: New Insights Into Obesity-Induced Lymphedema.

A two-way connection between obesity and lymphatic dysfunction has now been established. Clinical studies have demonstrated that obesity significantly increases the risk for developing secondary lymphedema. Using animal-models, obesity and metabolic syndrome have been linked to different aspects of lymphatic structural abnormalities and lymphatic dysfunction, including impaired contractility, impaired flow-mediated responses, impaired fluid transport, as well as increased permeability, and abnormal dendritic cell migration among others. Dysfunction of lymphatic valves is a main form of lymphatic dysfunction, known to result in severe edematous phenotypes; however, the extent of lymphatic valve deficiency in secondary lymphedema, including obesity-induced lymphedema, remains unknown. Therefore, the aims of the present study were 1) to determine whether western diet-induced obesity results in lymphatic valve dysfunction, and 2) to determine whether lymphatic valve dysfunction in western diet-induced obesity results from the diet itself, or as a consequence of the metabolic alterations induced by the diet. First, we quantitatively assessed and compared valve function in isolated popliteal and mesenteric collecting lymphatic vessels from control and western diet-induced obese C57BL/6J (WT) mice. Feeding a western diet for 14 weeks induced obesity and elevated plasma glucose and cholesterol levels when compared to controls. The function of lymphatic valves in popliteal lymphatics was not affected by diet-induced obesity; however, significant back-leak of pressure was observed in mesenteric lymphatic valves. Dysfunctional, leaky valves from obese animals also required significantly higher adverse pressure to trigger valve closure. Importantly, when subjected to treatment with a western diet, globally deficient PAI-1 mice were significantly protected against metabolic dysfunction and displayed fully functional, competent mesenteric lymphatic valves. In conclusion, our findings show for the first time that, in association with the metabolic alterations induced by the western diet, lymphatic valve dysfunction can be a critical component of obesity-induced lymphedema.

Colesevelam ameliorates non-alcoholic steatohepatitis and obesity in mice

BackgroundObesity, non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH) are important causes of morbidity and mortality worldwide. Bile acid dysregulation is a pivotal part in their pathogenesis. The aim of this study was to evaluate the bile acid sequestrant colesevelam in a microbiome-humanized mouse model of diet-induced obesity and steatohepatitis.MethodsGerm-free C57BL/6 mice were associated with stool from patients with NASH and subjected to 20 weeks of Western diet feeding with and without colesevelam.ResultsColesevelam reduced Western diet-induced body and liver weight gain in microbiome-humanized mice compared with controls. It ameliorated Western diet-induced hepatic inflammation, steatosis, fibrosis and insulin resistance. Colesevelam increased de novo bile acid synthesis and decreased hepatic cholesterol content in microbiome-humanized mice fed a Western diet. It further induced the gene expression of the antimicrobials Reg3g and Reg3b in the distal small intestine and decreased plasma levels of LPS.ConclusionsColesevelam ameliorates Western diet-induced steatohepatitis and obesity in microbiome-humanized mice.

Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ.

Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1S231A-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease.

Insulin-like growth factor-1 short-period therapy stimulates bone marrow cells in obese swiss mice.

Bone marrow cells (BMCs) from obese Swiss mice fed with Western diet show mitochondrial dysfunction. Obesity interferes with BMCs disrupting energetic metabolism, stimulating apoptosis, and reducing cell proliferation since adipose tissue releases inflammatory adipokines into the medullar microenvironment. These changes lead to reduction of BMC differentiation capacity and hematopoiesis impairment, a process responsible for blood cell continuous production through hematopoietic stem cells (HSCs). This work aimed to analyze the effects of IGF-1 therapy on BMC viability in Western diet-induced obesity, in vivo. We observed that after only 1week of treatment, obese Swiss mice presented reduced body weight and visceral fat and increased mitochondrial oxidative capacity and coupling, indicating mitochondrial function improvement. In addition, IGF-1 was able to reduce apoptosis of total BMCs, stem cell subpopulations (hematopoietic and mesenchymal), and leukocytes, restoring all progenitor hematopoietic lineages. The treatment also contributed to increase proliferative capacity of hematopoietic stem cells and leukocytes, keeping the hematopoietic and immune systems balanced. Therefore, we conclude that IGF-1 short period therapy improved BMC survival, proliferation, and differentiation capacity in obese Swiss mice.