Liver Of Obese Mice Research Articles

Adipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects

Thyroid hormone (TH) is a thermogenic activator with anti-obesity potential. However, systemic TH administration has no obvious clinical benefits on weight reduction. Herein we selectively delivered triiodothyronine (T3) to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3). Systemic T3 administration failed to promote thermogenesis in brown and white adipose tissues (WAT) due to a feedback suppression of sympathetic innervation. PLT3 therapy effectively obviated this feedback suppression on adrenergic inputs, and potently induced browning and thermogenesis of WAT, leading to alleviation of obesity, glucose intolerance, insulin resistance, and fatty liver in obese mice. Furthermore, PLT3 was much more effective than systemic T3 therapy in reducing hypercholesterolemia and atherosclerosis in apoE-deficient mice. These findings uncover WAT as a viable target mediating the therapeutic benefits of TH and provide a safe and efficient therapeutic strategy for obesity and its complications by delivering TH to adipose tissue.

Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

BackgroundIn mouse liver hepatocytes, nearly half of the surface area of every mitochondrion is covered by wrappER, a wrapping-type of ER that is rich in fatty acids and synthesizes lipoproteins (VLDL) (Anastasia et al. in Cell Rep 34:108873, 2021; Hurtley in Science (80- ) 372:142–143, 2021; Ilacqua et al. in J Cell Sci 135:1–11, 2021). A disruption of the ultrastructure of the wrappER-mitochondria contact results in altered fatty acid flux, leading to hepatic dyslipidemia (Anastasia et al. 2021). The molecular mechanism that regulates the extent of wrappER-mitochondria contacts is unknown.MethodsWe evaluated the expression level of the mitochondrial protein Synj2bp in the liver of normal and obese (ob/ob) mice. In addition, we silenced its expression in the liver using an AAV8 vector. We coupled quantitative EM morphometric analysis to proteomics and lipid analyses on these livers.ResultsThe expression level of Synj2bp in the liver positively correlates with the extent of wrappER-mitochondria contacts. A 50% reduction in wrappER-mitochondria contacts causes hepatic dyslipidemia, characterized by a gross accumulation of lipid droplets in the liver, an increased hepatic secretion of VLDL and triglycerides, a curtailed ApoE expression, and an increased capacity of mitochondrial fatty acid respiration.ConclusionSynj2bp regulates the extent of wrappER-mitochondria contacts in the liver, thus contributing to the control of hepatic lipid flux.

Abstract 13042: Circulating Obesity Associated Pro-Fibrotic Protein as a Brown Adipokine Promotes Liver and Heart Fibrosis in Obese Nash Mice

Introduction: Non-alcoholic steatohepatitis (NASH), driven by the obesity epidemic, has become the most common form of liver disease. Excessive calorie intake inflames visceral adipose tissue, and let this organ produce pro-inflammatory adipokines. Brown adipose tissue (BAT) is another type of fat pad equipped with the thermogenic capacity, and the role of BAT-derived adipokines (BATokines) in pathogenesis of NASH remains to be explored. Hypothesis: Various kinds of white adipokines are known in obesity. However, BATokines in pathogenesis of NASH still remain to be explored. Methods: To identify the function of obesity associated pro-fibrotic protein (OAFP), we generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice, and murine OAFP knockout (KO) model. We also conducted functional in vitro studies with differentiated brown adipocytes. Results: Here we identified a secreted type pro-fibrotic protein OAFP, as one of the BATokines contributing for the promotion of liver fibrosis in a murine NASH model. We also found that OAFP increased in circulation of human NASH patients. Genetic models with OAFP suppression ameliorated liver fibrosis, in contrast, OAFP gain of function model enhanced this in our NASH model. In addition, we found that cardiac fibrosis also developed in the NASH model, and this was ameliorated in OAFP-KO model, indicating the pathogenic role of OAFP in heart failure with preserved ejection fraction (HFpEF). Our biobank studies also showed OAFP increased in HFpEF patients. We also found ER stress-mediated signaling enhanced the production of this BATokine. Conclusions: Our results testing mice models, and human studies indicate suppression of OAFP becomes therapies for HFpEF and NASH.

Abstract 12619: Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9, Obesity or Not

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis. Cilostazol exerts favorable cellular and metabolic effects; however, the effect of cilostazol on the expression of PCSK9 has not been previously reported. Hypothesis: Our study aimed to investigate the potential mechanisms of action of cilostazol on the expression of PCSK9 and lipid homeostasis. Methods: We evaluated the effects of cilostazol on the expression of PCSK9 in HepG2 cells and evaluated potential molecular mechanisms by measuring signaling molecules in the liver and serum lipid profiles in high-fat diet-induced obese mice and normal chow-fed mice. Additionally, the baseline and post-treatment serum PCSK9 levels of obese and non-obese human participants treated with cilostazol were measured. Results: Cilostazol treatment significantly induced the messenger RNA and protein expression of PCSK9 in HepG2 cells and enhanced PCSK9 promoter activity. Chromatin immunoprecipitation assays confirmed that cilostazol treatment enhanced PCSK9 transcription by binding to peroxisome proliferator-activated receptor-γ (PPARγ) via the PPARγ DNA response element. PPARγ knockdown attenuated the stimulatory effect of cilostazol on PCSK9. In vivo experiments revealed that cilostazol treatment increased serum levels of PCSK9 in normal mice but significantly reduced PCSK9 levels in obese mice (Figure). Clinical data showed that cilostazol treatment significantly reduced serum PCSK9 levels in patients with obesity. The expressions of relevant miRNAs also showed consistent results. Conclusions: The obesity-dependent effects of cilostazol on PCSK9 expression observed from bench to bedside demonstrate the therapeutic potential of cilostazol in clinical settings.

Transdermal Delivery of Succinate Accelerates Energy Dissipation of Brown Adipocytes to Reduce Remote Fat Accumulation.

Weight loss by increasing energy consumption of thermogenic adipocytes to overcome obesity remains a challenge. Herein, we established a transdermal device that was based on the local and temporarily controlled delivery of succinate (SC), a tricarboxylic acid cycle metabolic intermediate to stimulate the thermogenesis pathway of uncoupling protein 1 (UCP1) and accelerate energy dissipation of brown adipose tissue (BAT) under the dorsal interscapular skin, further initiating the consumption of fatty acids by systemic metabolism. SC microneedle patches significantly suppressed weight gain and fat accumulation of remote organs, including liver and peripheral white adipose tissue (WAT) in high-fat diet-induced obese mice. mRNA expression levels of Ucp1 in BAT and other browning markers in WAT were significantly elevated in the mice that were treated with SC microneedle. Thus, the energy dissipation of BAT using UCP1-mediated thermogenesis accelerated by the transdermal delivery of SC may become a potential and effective strategy for preventing obesity.

Anti-diabetic effect of hesperidin on palmitate (PA)-treated HepG2 cells and high fat diet-induced obese mice

The present study examined the relationship between the anti-diabetic effect of hesperidin (HES) and the differential gene expression in HES treated high fat diet (HFD)-induced obese mice. Based on the glucose uptake assay, the treatment of HES restored the glucose uptake to control level in an insulin-independent manner in PA-treated HepG2 cells. Western blot analysis confirmed that the treatment of HES increased the insulin-stimulated phosphorylation of Akt and GSK3β in insulin-resistant PA-treated HepG2 cells. HFD-induced obese mice treated with HES significantly reduced serum insulin, blood glucose, and homeostatic model assessment for insulin resistance (HOMA-IR) values. In addition, both glucose tolerance and insulin tolerance were significantly improved to normal level by HES in HFD-induced obese mice. RNA sequencing analysis disclosed that the expression levels of up-regulated 12 genes and down-regulated 6 genes related to insulin signaling and glucose metabolism were restored to normal level by HES in the liver of HFD-induced obese mice. A protein–protein interaction (PPI) network was constructed via search tool for the retrieval of interacting genes/proteins (STRING) analysis, and Eno1, Pik3cd, Hk2, Trib3, Myc, Nos3, Ppargc1a, and Igf2 were located in the functional hubs of the PPI network of glucose metabolism. Furthermore, Western blot analysis confirmed that HES improved insulin sensitivity and glucose homeostasis by normalizing the expression levels of hexokinase-II, enolase-1, and PI3 kinase p110δ to normal level. The overall results suggest that HES possess a potential anti-diabetic effect by normalizing the expression levels of the insulin signaling and glucose metabolism related genes which were perturbed in the liver of HFD-induced obese mice.

FOXO1 is downregulated in obese mice subjected to short-term strength training.

Obesity is a worldwide health problem and is directly associated with insulin resistance and type 2 diabetes. The liver is an important organ for the control of healthy glycemic levels, since insulin resistance in this organ reduces phosphorylation of forkhead box protein 1(FOXO1) protein, leading to higher hepatic glucose production (HGP) and fasting hyperglycemia. Aerobic physical training is known as an important strategy in increasing the insulin action in the liver by increasing FOXO1 phosphorylation and reducing gluconeogenesis. However, little is known about the effects of strength training in this context. This study aimed to investigate the effects of short-term strength training on hepatic insulin sensitivity and glycogen synthase kinase-3β(GSK3β) and FOXO1 phosphorylation in obese (OB) mice. To achieve this goal, OB Swiss mice performed the strength training protocol (one daily session for 15 days). Short-term strength training increased the phosphorylation of protein kinase B and GSK3β in the liver after insulin stimulus and improved the control of HGP during the pyruvate tolerance test. On the other hand, sedentary OB animals reduced FOXO1 phosphorylation and increased the levels of nuclear FOXO1 in the liver, increasing the phosphoenolpyruvate carboxykinase(PEPCK) and glucose-6-phosphatase (G6Pase) content. The bioinformatics analysis also showed positive correlations between hepatic FOXO1 levels and gluconeogenic genes, reinforcing our findings. However, strength-trained animals reverted to this scenario, regardless of body adiposity changes. In conclusion, short-term strength training is an efficient strategy to enhance the insulin action in the liver of OB mice, contributing to glycemic control by reducing the activity of hepatic FOXO1 and lowering PEPCK and G6Pase contents.

CCN1/Integrin α5β1 Instigates Free Fatty Acid-Induced Hepatocyte Lipid Accumulation and Pyroptosis through NLRP3 Inflammasome Activation

Hyperlipidemia with high blood levels of free fatty acids (FFA) is the leading cause of non-alcoholic steatohepatitis. CCN1 is a secreted matricellular protein that drives various cellular functions, including proliferation, migration, and differentiation. However, its role in mediating FFA-induced pro-inflammatory cell death and its underlying molecular mechanisms have not been characterized. In this study, we demonstrated that CCN1 was upregulated in the livers of obese mice. The increase in FFA-induced CCN1 was evaluated in vitro by treating hepatocytes with a combination of oleic acid and palmitic acid (2:1). Gene silencing using specific small interfering RNAs (siRNA) revealed that CCN1 participated in FFA-induced intracellular lipid accumulation, caspase-1 activation, and hepatocyte pyroptosis. Next, we identified integrin α5β1 as a potential receptor of CCN1. Co-immunoprecipitation demonstrated that the binding between CCN1 and integrin α5β1 increased in hepatocytes upon FFA stimulation in the livers of obese mice. Similarly, the protein levels of integrin α5 and β1 were increased in vitro and in vivo. Experiments with specific siRNAs confirmed that integrin α5β1 played a part in FFA-induced intracellular lipid accumulation, NLRP3 inflammasome activation, and pyroptosis in hepatocytes. In conclusion, these results provide novel evidence that the CCN1/integrin α5β1 is a novel mediator that drives hepatic lipotoxicity via NLRP3-dependent pyroptosis.

Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9 between Obesity and Non-Obesity.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis. Cilostazol exerts favorable cellular and metabolic effects; however, the effect of cilostazol on the expression of PCSK9 has not been previously reported. Our study aimed to investigate the potential mechanisms of action of cilostazol on the expression of PCSK9 and lipid homeostasis. We evaluated the effects of cilostazol on the expression of PCSK9 in HepG2 cells and evaluated potential molecular mechanisms by measuring signaling molecules in the liver and serum lipid profiles in high-fat diet-induced obese mice and normal chow-fed mice. Cilostazol treatment significantly induced the messenger RNA and protein expression of PCSK9 in HepG2 cells and enhanced PCSK9 promoter activity. Chromatin immunoprecipitation assays confirmed that cilostazol treatment enhanced PCSK9 transcription by binding to peroxisome proliferator-activated receptor-γ (PPARγ) via the PPARγ DNA response element. PPARγ knockdown attenuated the stimulatory effect of cilostazol on PCSK9. In vitro, cilostazol treatment increased PCSK9 expression in vehicle-treated HepG2 cells but decreased PCSK9 expression in palmitic acid-treated HepG2 cells. In vivo, cilostazol treatment increased the serum levels of PCSK9 in normal mice but significantly reduced PCSK9 levels in obese mice. The expressions of PCSK9-relevant microRNAs also showed similar results. Clinical data showed that cilostazol treatment significantly reduced serum PCSK9 levels in patients with obesity. The obesity-dependent effects of cilostazol on PCSK9 expression observed from bench to bedside demonstrates the therapeutic potential of cilostazol in clinical settings.

Somatic ablation of IKKβ in liver and leukocytes is not tolerated in obese mice but hepatic IKKβ deletion improves fatty liver and insulin sensitivity.

The kinase IKKβ controls pro-inflammatory gene expression, and its activity in the liver and leukocytes was shown to drive metabolic inflammation and insulin resistance in obesity. However, it was also proposed that liver IKKβ signaling protects obese mice from insulin resistance and endoplasmic reticulum (ER) stress by increasing XBP1s protein stability. Furthermore, mice lacking IKKβ in leukocytes display increased lethality to lipopolysaccharides. This study aims at improving our understanding of the role of IKKβ signaling in obesity. We induced IKKβ deletion in hematopoietic cells and liver of obese mice by Cre-LoxP recombination, using an INF-inducible system, or a liver-specific IKKβ deletion in obese mice by adenovirus delivery of the Cre recombinase. The histopathological, immune, and metabolic phenotype of the mice was characterized. IKKβ deletion in the liver and hematopoietic cells was not tolerated in mice with established obesity exposed to the TLR3 agonist poly(I:C) and exacerbated liver damage and ER-stress despite elevated XBP1s. By contrast, liver-specific ablation of IKKβ in obese mice reduced steatosis and improved insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of de-novo lipogenesis genes. We conclude that IKKβ blockage in liver and leukocytes is not tolerated in obese mice exposed to TLR3 agonists. However, selective hepatic IKKβ ablation improves fatty liver and insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of lipogenic genes.

Pathogenic effects of Desulfovibrio in the gut on fatty liver in diet-induced obese mice and children with obesity.

Although we know the key role of gut dysbiosis in nonalcoholic fatty liver disease (NAFLD), it remains unclear what microbe(s) are responsible. This study aims to identify the microbes that cause NAFLD. C57BL/6JNarl male mice fed a high-fat diet (HFD) were orally administered Lactobacillus reuteri (L. reuteri) or Lactobacillus rhamnosus GG plus Bifidobacterium animalis subsp. lactis BB12 (LGG plus BB12). Their fecal microbiomes identified by 16S rRNA sequencing were correlated with the severity of fatty liver. We then used a human cohort to confirm the role of the microbe(s). The HFD-fed mice were administrated with the identified bacterium, Desulfovibrio. The histopathological changes in the liver and ileum were analyzed. Lactobacillus and Bifidobacterium improved hepatic steatosis and fibrosis in HFD-fed mice, which was related to the decreased abundance of Desulfovibrio in feces. Further human study confirmed the amount of D. piger in the fecal microbiota of obese children with NAFLD was increased. We then administered D. piger and found aggravated hepatic steatosis and fibrosis in HFD-fed mice. Hepatic expression of CD36 was significantly increased in HFD-fed mice gavaged with D. piger. In HepG2 cells, overexpression of CD36 increased lipid droplets, whereas knockdown of CD36 decreased lipid droplets. HFD-fed mice gavaged with D. piger had a decrease in the villus length, crypt depth, and zonula occludens-1 density in the ileum tissue. Our findings provide novel insights into the role of Desulfovibrio dysregulation in NAFLD. Modulation of Desulfovibrio may be a potential target for the treatment of NAFLD.

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition.

BackgroundEctopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.MethodsWe used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.ResultsANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.ConclusionsANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

Hepatocyte Rap1a contributes to obesity- and statin-associated hyperglycemia.

SUMMARYExcessive hepatic glucose production contributes to the development of hyperglycemia and is a key feature of type 2 diabetes. Here, we report that activation of hepatocyte Rap1a suppresses gluconeogenic gene expression and glucose production, whereas Rap1a silencing stimulates them. Rap1a activation is suppressed in obese mouse liver, and restoring its activity improves glucose intolerance. As Rap1a′s membrane localization and activation depends on its geranylgeranylation, which is inhibited by statins, we show that statin-treated hepatocytes and the human liver have lower active-Rap1a levels. Similar to Rap1a inhibition, statins stimulate hepatic gluconeogenesis and increase fasting blood glucose in obese mice. Geranylgeraniol treatment, which acts as the precursor for geranylgeranyl isoprenoids, restores Rap1a activity and improves statin-mediated glucose intolerance. Mechanistically, Rap1a activation induces actin polymerization, which suppresses gluconeogenesis by Akt-mediated FoxO1 inhibition. Thus, Rap1a regulates hepatic glucose homeostasis, and blocking its activity, via lowering geranylgeranyl isoprenoids, contributes to statin-induced glucose intolerance.

Resistance exercise attenuates IKKε phosphorylation and hepatic fat accumulation of obese mice.

Obesity is associated with low-grade inflammation and disturbances in hepatic metabolism. This study aimed to investigate the effects of resistance exercise on inflammatory signalling related to IκB kinase (IKK) ɛ protein (IKKɛ) and on hepatic fat accumulation in obese mice. Male Swiss mice were distributed into three groups: control (CTL) fed with standard chow; obese (OB) mice induced by a high-fat diet (HFD); obese exercised (OB + RE) mice fed with HFD and submitted to a resistance exercise training. The resistance exercise training protocol consisted of 20 sets/3 ladder climbs for 8 weeks, three times/week on alternate days. The training overload was equivalent to 70% of the maximum load supported by the rodent. Assays were performed to evaluate weight gain, hepatic fat content, fasting glucose, insulin sensitivity, IKKɛ phosphorylation and proteins related to insulin signalling and lipogenesis in the liver. Mice that received the high-fat diet showed greater adiposity, impaired insulin sensitivity, increased fasting glucose and increased hepatic fat accumulation. These results were accompanied by an increase in IKKɛ phosphorylation and lipogenesis-related proteins such as cluster of differentiation 36 (CD36) and fatty acid synthase (FAS) in the liver of obese mice. In contrast, exercised mice showed lower body weight and adiposity evolution throughout the experiment. In addition, resistance exercise suppressed the effects of the high-fat diet by reducing IKKɛ phosphorylation and hepatic fat content. In conclusion, resistance exercise training improves hepatic fat metabolism and glycaemic homeostasis, which are, at least in part, linked to the anti-inflammatory effect of reduced IKKɛ phosphorylation in the liver of obese mice.

AMPK-PPARγ-Cidec Axis Drives the Fasting-Induced Lipid Droplet Aggregation in the Liver of Obese Mice.

Intermittent fasting is one of the most common clinical treatments for the obesity, a main risk factor of the metabolic syndrome which can lead to a variety of diseases. Fasting-induced fat mobilization alters the metabolic state of lipid in the liver, predisposing to increase the hepatic lipid droplet aggregation and triglyceride levels. However, the underlying mechanisms regarding the lipid droplet aggregation in the liver after fasting remains elusive. Here, we report that a lipid droplet surface binding protein Cidec (cell death inducing DFFA like effector C) is activated by AMPK to regulate the hepatic lipid droplet fusion following fasting in obese mice. Specifically, we found that lipid droplets were significantly aggregated in the liver of high-fat-diet and ob/ob mice after 16 and 24 h of fasting, accompanied by the dramatically up-regulated expression of Cidec. Consistently, overexpression of Cidec in the AML12 cells resulted in the intracellular lipid droplet aggregation. Furthermore, we showed that fasting caused the up-regulated expression of AMPK, which in turn activated the transcription of Cidec through the transcription factor PPARγ. Altogether, our observations reveal that fasting-induced hepatic lipid droplet aggregation is mediated by the AMPK-activated expression of Cidec via PPARγ, extending our understanding about the molecular mechanism of the impact of fasting on the obesity and providing potential targets for the treatment of human obesity.

Efficacy and safety of guanabenz acetate treatment for non-alcoholic fatty liver disease: a study protocol for a randomised investigator-initiated phase IIa study

IntroductionNon-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of...

FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity

Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (UPR) signaling contribute to the development of type 2 diabetes in obesity. UPR signaling is a complex signaling pathway, which is still being explored in many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.

Diabesity? No worries, FKBP11 to the rescue

Obesity-induced type 2 diabetes, or diabesity, is associated with ER stress, UPR activation, and insulin resistance through poorly understood mechanisms. Herrema etal. (2022) report that the XBP1 target FKBP11 is repressed in the obese mouse liver and that its re-expression activates a protective UPR pathway that restores insulin sensitivity.

Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation.

Autophagy is a fundamental housekeeping process by which cells degrade their components to maintain homeostasis. Defects in autophagy have been associated with aging, neurodegeneration and metabolic diseases. Non-alcoholic fatty liver diseases (NAFLDs) are characterized by hepatic fat accumulation with or without inflammation. No treatment for NAFLDs is currently available, but autophagy induction has been proposed as a promising therapeutic strategy. Here, we aimed to design autophagy-inducing particles, using the autophagy-inducing peptide (Tat-Beclin), and achieve liver targeting in vivo, taking NAFLD as a model disease. Polylactic acid (PLA) particles were prepared by nanoprecipitation without any surfactant, followed by surface peptide adsorption. The ability of Tat-Beclin nanoparticles (NP T-B) to modulate autophagy and to decrease intracellular lipid was evaluated in vitro by LC3 immunoblot and using a cellular model of steatosis, respectively. The intracellular localization of particles was evaluated by transmission electron microscopy (TEM). Finally, biodistribution of fluorescent NP T-B was evaluated in vivo using tomography in normal and obese mice. The results showed that NP T-B induce autophagy with a long-lasting and enhanced effect compared to the soluble peptide, and at a ten times lower dose. Intracellular lipid also decreased in a cellular model of NAFLD after treatment with T-B and NP T-B under the same dose conditions. Ultrastructural studies revealed that NP T-B are internalized and located in endosomal, endolysosomal and autolysosomal compartments, while in healthy and obese mice, NP T-B could accumulate for several days in the liver. Given the beneficial effects of autophagy-inducing particles in vitro, and their capacity to target the liver of normal and obese mice, NP T-B could be a promising therapeutic tool for NAFLDs, warranting further in vivo investigation.

Higd1a facilitates exercise-mediated alleviation of fatty liver in diet-induced obese mice

BackgroundNonalcoholic fatty liver disease (NAFLD) has emerged as the most common liver disease. Exercise is an effective strategy against NAFLD, but its underlying molecular mechanism is not completely understood. MethodsHigd1a, a mitochondrial inner membrane protein, was knocked down or overexpressed in mice livers by tail vein injection of adeno-associated virus (AAV) vectors. High fat diet-induced obese mice were subjected to treadmill training. Alpha mouse liver 12 (AML12) cells were used for in vitro studies. ResultsHigd1a was upregulated in mice livers after treadmill exercise training. Knockdown of Higd1a in diet-induced obese mice livers impaired exercise-mediated alleviation of hepatic steatosis, liver injury and inflammation. On the contrary, hepatic overexpression of Higd1a ameliorated fatty liver, liver injury and inflammation in synergy with exercise. Mechanistically, deficiency of Higd1a in hepatocytes promoted free fatty acids (FFAs)-induced apoptosis and oxidative stress, and elevated the cytosolic level of oxidized mitochondrial DNA (ox-mtDNA) to activate NLRP3 inflammasome and JNK signaling, leading to decreased expression of critical genes involved in fatty acid oxidation (FAO), such as Ppara, Cpt1a and Acadm. Overexpression of Higd1a in hepatocytes blunted the above effects, which ultimately increased FAO genes expression and alleviated fat accumulation in hepatocytes. ConclusionThese results identify a Higd1a-mediated inhibition of cytosolic ox-mtDNA/NLRP3 inflammasomes/JNK pathway that facilitates exercise-mediated alleviation of hepatosteatosis.