Insulin Resistance In Obesity Research Articles

Piperine attenuates hepatic steatosis and insulin resistance in high-fat diet-induced obesity in Sprague-Dawley rats

Substantial evidence suggests that pepper consumption is associated with a reduced risk of obesity-related complications. However, whether piperine, the main component of pepper, improves obesity-induced hepatic lipid accumulation and insulin resistance and the action mechanism of piperine still remain unclear. We hypothesized that piperine attenuates high-fat diet (HFD)-induced obesity and improves the related metabolic complications in HFD-induced obese rats. Adult Sprague-Dawley (SD) male rats were fed a control diet (CON) or an HFD for 16 weeks. Obese rats were divided into 4 groups: HFD and HFD with daily gavage of piperine 2.7 mg/kg body weight (PIP-Low), 13.5 mg/kg body weight (PIP-Medium), and 27 mg/kg body weight (PIP-High) for another 8 weeks. Rats were euthanized after an 8-hour fast, and the liver, heart, kidney, and white adipose tissue were collected and stored at –80 °C. Piperine administration significantly reduced weight gain, plasma insulin, and glucose concentration. For oral piperine at a dose of 27 mg/kg body weight, body weight significantly decreased by 5.7% compared with that in the HFD group. Additionally, oral piperine administration considerably reduced serum triglyceride concentration. Furthermore, piperine administration reversed the HFD-induced downregulation of adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling molecules and increased the plasma levels of adiponectin and the messenger RNA expression of the adiponectin receptor; additionally, it increased the phosphorylation of phosphatidylinositol-3 kinase (PI3K) and protein kinase B. Overall, oral piperine administration reversed HFD-induced liver lipid accumulation and insulin resistance, possibly via the inactivation of adiponectin-AMPK and PI3K-Akt signaling. These findings imply that piperine could serve as an effective agent for healthy weight loss.

Netrin-1 Promotes Visceral Adipose Tissue Inflammation in Obesity and Is Associated with Insulin Resistance.

Netrin (NTN)-1 exhibits pro- and anti-inflammatory roles in different settings, playing important roles in the obesity-associated low-grade chronic inflammation. We aimed to determine the impact of NTN-1 on obesity and obesity-associated type 2 diabetes, as well as its role in visceral adipose tissue (VAT) inflammation. A total of 91 subjects were enrolled in this case-control study. Circulating levels of NTN-1 and its receptor neogenin (NEO)-1 were determined before and after weight loss achieved by caloric restriction and bariatric surgery. mRNA levels of NTN1 and NEO1 were assessed in human VAT, liver, and peripheral blood mononuclear cells. In vitro studies in human visceral adipocytes and human monocytic leukemia cells (THP-1)-derived macrophages were performed to analyze the impact of inflammation-related mediators on the gene expression levels of NTN1 and its receptor NEO1 as well as the effect of NTN-1 on inflammation. Increased (p < 0.001) circulating concentrations of NTN-1 in obesity decreased (p < 0.05) after diet-induced weight loss being also associated with a reduction in glucose (p < 0.01) and insulin levels (p < 0.05). Gene expression levels of NTN1 and NEO1 were upregulated (p < 0.05) in the VAT from patients with obesity with the highest expression in the stromovascular fraction cells compared with mature adipocytes (p < 0.01). NTN1 expression levels were enhanced (p < 0.01) under hypoxia and by inflammatory factors in both adipocytes and macrophages. Adipocyte-conditioned media strongly upregulated (p < 0.001) the mRNA levels of NTN1 in macrophages. The treatment of adipocytes with NTN-1 promoted the upregulation (p < 0.05) of pro-inflammatory and chemotactic molecules as well as its receptor NEO1. Collectively, these findings suggest that NTN-1 regulates VAT chronic inflammation and insulin resistance in obesity.

Insulin Resistance in Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) is one of the readily recognised endocrine gland illnesses in women, with an incidence range from 2.2% to 26% in India. Patients experiencing PCOS experience issues involving irregular menstrual periods, hirsutism, acne, being overweight, and impotence. Long-term, low-grade inflammation has emerged as a crucial factor leading to PCOS. A rise in glucose levels may stimulate oxidative stress and a troubling reaction from mononuclear cells (MNC) of females with PCOS, which normally do not rely on fat. This is required because MNC-derived macrophages are the major source of cytokine synthesis in big adipose tissue and similarly encourage adipocyte cytokine production. In summary, data reveal the substantial risks of insulin resistance in obese people who are suffering from PCOS. The findings of this specific lesson indicated that individuals with the conventional PCOS phenotype had obesity and higher insulin levels and insulin resistance, neglecting the absence of BMI differences from other phenotypes. These data show that insulin resistance is the most significant pathophysiological trait in people with PCOS.

Effect of Nutritional Rehabilitation on Osteocalcin and Insulin Resistance in Pediatric Obesity

Children's obesity and overweight are new health issues and are associated with insulin resistance. Osteocalcin level is inversely correlated with obesity and has a metabolic role in insulin resistance.

Calreticulin and PDIA3, two markers of endoplasmic reticulum stress, are associated with metabolic alterations and insulin resistance in pediatric obesity: A pilot study.

Our aim was to evaluate the markers of endoplasmic reticulum (ER) stress among children and adolescents with obesity in relation to metabolic alterations. Calreticulin (CALR) and PDIA3 circulating levels were assessed on 52 pediatric subjects—26 patients with obesity and 26 normal weight controls (4–18 years)—enrolled in a pilot study. Clinical and metabolic evaluations were performed (BMI-SDS, insulin, and glucose at fasting and during an oral glucose tolerance test, lipid profile, blood pressure), and metabolic syndrome was detected. PDIA3 was higher (p < 0.02) and CALR slightly higher in children with obesity than in controls. PDIA3 was related positively to the Tanner stages. Both PDIA3 and CALR were positively associated with insulin resistance, cholesterol, and triglycerides and the number of criteria identifying metabolic syndrome and negatively with fasting and post-challenge insulin sensitivity. Our preliminary findings suggest the existence of a link between ER stress and metabolic changes behind obesity complications even at the pediatric age. CALR and PDIA3 could be early markers of insulin resistance and dyslipidemia-related ER stress useful to stratify patients at high risk of further complications.

The role of probiotic supplementation on insulin resistance in obesity associated diabetes: A mini review

Obesity and diabetes are two metabolic disorders linked by an inflammatory process named insulin resistance (IR). Various research on the role of gut microbiota in developing obesity and its associated disorders has led to the growing interest in probiotic supplementation. Considering the life-threatening complications of diabesity this mini review explored the effects of probiotic supplementation on IR in obesity associated diabetes. This review is based on recent articles from 2005-2020, studying the role of probiotic supplementation on glucose and insulin parameters in healthy and diabetic mouse model. Probiotic supplementation altered the gut microbiota composition, increased short chain fatty acid production, and decreased pro inflammatory cytokines. Additionally, they decreased intestinal permeability, circulating lipopolysaccharides and metabolic endotoxemia, hence improved insulin sensitivity and reduced obesity. Although multi-strain probiotic supplementation showed greater benefits than single strain interventions, variations in the concentration of probiotics used and the duration of treatment also influenced the results. Probiotic supplementation could manipulate the gut microbiota by reducing intestinal permeability, inflammation and ameliorate IR and obesity associated diabetes in animal models which requires further long-term clinical studies in humans.

Sclerostin aggravates insulin signaling in skeletal muscle and hepatic steatosis via upregulation of ER stress by mTOR-mediated inhibition of autophagy under hyperlipidemic conditions.

Recently, sclerostin (SCL), a circulating glycoprotein, was proposed to be a novel myokine involved in developing metabolic disorders. The association between SCL levels and insulin resistance in skeletal muscle, liver, and adipose tissue was studied in individuals with aggravated glucose tolerance. Thus, we hypothesized that elevated circulating SCL might affect skeletal muscle insulin signaling and hepatic lipid metabolism, and aimed to investigate the effects of SCL on skeletal muscle insulin resistance and hepatic steatosis in obesity using in vitro and in vivo experimental models under hyperlipidemic conditions. In the current study, we found elevated SCL messenger RNA expression levels in myocytes in obese patients. In addition to a higher blood level, SCL was expressed at an elevated level in the skeletal muscle of mice fed a high-fat diet (HFD). Higher SCL release levels and expression were also noticed in palmitate-treated C2C12 myocytes. SCL suppression by in vivo transfection improves skeletal muscle insulin resistance and hepatic steatosis in HFD-fed mice. The treatment of C2C12 myocytes with recombinant SCL aggravated insulin signaling. Furthermore, treatment with SCL augmented lipogenic lipid deposition in human primary hepatocytes. Treatment with SCL upregulated mammalian target of rapamycin (mTOR) phosphorylation and suppressed autophagy markers, thereby causing endoplasmic reticulum (ER) stress. 4-Phenylbutyric acid, a pharmacological ER stress inhibitor, abolished the effects of SCL on insulin signaling in C2C12 myocytes and lipid accumulation in primary hepatocytes. In conclusion, SCL promotes skeletal muscle insulin resistance and hepatic steatosis by upregulating ER stress via the mTOR/autophagy-mediated pathway. The present study suggests that antagonizing SCL might be a novel therapeutic strategy for simultaneously managing insulin resistance and hepatic steatosis in obesity.

Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review.

Obesity–insulin resistance–β-cells apoptosis” is an important trilogy of the pathogenesis of type 2 diabetes. With the global pandemic of obesity and diabetes, continuous research and development of new drugs focuses on the prevention of the pathological progress of these diseases. According to a recent study, the natural product kaempferol has excellent antidiabetic effects. Therefore, this review comprehensively summarized the frontier studies and pharmacological mechanisms of kaempferol in the treatment of diabetes. The successful research and development of kaempferol may yield a significant leap in the treatment of diabetes and its complications.

Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis.

Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions; however, whether MAM dysfunction plays a causal role in hepatic insulin resistance and steatosis is not clear. Thus, we aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment. We analyzed hepatic ER-mitochondria interactions and calcium exchange in a time-dependent and reversible manner in mice with diet-induced obesity. Additionally, we used recombinant adenovirus to express a specific organelle spacer or linker in mouse livers, to determine the causal impact of MAM dysfunction on hepatic metabolic alterations. Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in mice with diet-induced obesity. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type 2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index. ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could help to restore metabolic homeostasis. The literature suggests that interactions between the endoplasmic reticulum and mitochondria could play a role in hepatic insulin resistance and steatosis during chronic obesity. In the present study, we reappraised the time-dependent regulation of hepatic endoplasmic reticulum-mitochondria interactions and calcium exchange, investigating reversibility and causality, in mice with diet-induced obesity. We also assessed the relevance of our findings to humans. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis that can be improved by nutritional strategies.

Quantitative Structure-Activity Relationship Analysis of Isosteviol-Related Compounds as Activated Coagulation Factor X (FXa) Inhibitors.

Stevioside, one of the natural sweeteners extracted from stevia leaves, and its derivatives are considered to have numerous beneficial pharmacological properties, including the inhibition of activated coagulation factor X (FXa). FXa-PAR signaling is a possible therapeutic target to enhance impaired metabolism and insulin resistance in obesity. Thus, the goal of the investigation was a QSAR analysis using multivariate adaptive regression splines (MARSplines) applied to a data set of 20 isosteviol derivatives bearing thiourea fragments with possible FXa inhibitory action. The best MARS submodel described a strong correlation between FXa inhibitory activity and molecular descriptors, such as: B01[C-Cl], E2m, L3v, Mor06i, RDF070i and HATS7s. Five out of six descriptors included in the model are geometrical descriptors quantifying three-dimensional aspects of molecular structure, which indicates that the molecular three-dimensional conformation is of high significance for the MARSplines modeling procedure and obviously for FXa inhibitory activity. High model performance was confirmed through an extensive validation protocol. The results of the study not only confirmed the enhancement in pharmacological activity by the presence of chlorine in a phenyl ring, but also, and primarily, may provide the basis for searching for new active isosteviol analogues, which may serve as drugs or health-beneficial food additives in patients suffering from obesity and comorbidities.

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.

Regulation of Insulin Clearance by Non-Esterified Fatty Acids

Insulin stores lipid in adipocytes and prevents lipolysis and the release of non-esterified fatty acids (NEFA). Excessive release of NEFA during sustained energy supply and increase in abdominal adiposity trigger systemic insulin resistance, including in the liver, a major site of insulin clearance. This causes a reduction in insulin clearance as a compensatory mechanism to insulin resistance in obesity. On the other hand, reduced insulin clearance in the liver can cause chronic hyperinsulinemia, followed by downregulation of insulin receptor and insulin resistance. Delineating the cause–effect relationship between reduced insulin clearance and insulin resistance has been complicated by the fact that insulin action and clearance are mechanistically linked to insulin binding to its receptors. This review discusses how NEFA mobilization contributes to the reciprocal relationship between insulin resistance and reduced hepatic insulin clearance, and how this may be implicated in the pathogenesis of non-alcoholic fatty liver disease.

Novel approaches to optimize nutrition in the elderly patients

BACKGROUND: The current dietary advice for the elderly is not in line with contemporary understanding of the effects that nutrition produces on the universal mechanisms of age-related diseases.&#x0D; AIM: This review is designed to consider modern concepts on the impact of nutrition on the development of age-related diseases and compare them with the current dietary advice for the elderly, with special focus on prevention of frailty and sarcopenia, the key factors of longevity and health quality.&#x0D; METHODS: Search in Google Scholar and PubMed for reviews and clinical trials using the keywords nutrition, frailty, and sarcopenia.&#x0D; RESULTS: Frailty is affected by several biopsychosocial factors, with nutrition having the paramount role. It dominates the onset and progression of the key mechanisms of accelerated aging: most importantly, chronic systemic inflammation, insulin resistance, and gut dysbiosis. There is strong evidence that frailty is promoted by malnutrition (insufficiency of energy and nutrients), obesity (insulin resistance), protein deficit, high dietary inflammatory index, easily digested carbohydrates (including fructose and starch), highly processed food, and trans fats and indirectly by gluten. Frailty and sarcopenia can be prevented through the consumption of high-quality (animal) protein, vegetables and fruit (the source of dietary fiber, vitamins, minerals, and phytonutrients), fats, nutrients with antioxidant properties (including vitamins A and E, zinc, selenium, and omega-3 fatty acids), correction of vitamin D status, support of gut microbial diversity, correction of hyperinsulinemia, and increased intestinal permeability.&#x0D; CONCLUSION: The dietary advice for elderly patients requires revision in line with the contemporary understanding of mechanisms behind age-related diseases and the recent evidence base. This review covers the basics of nutrition essential to prevent frailty and sarcopenia.

Adiponectin, the adiponectin paradox, and Alzheimer's Disease: Is this association biologically plausible?

Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox.

Leptin mediates the regulation of muscle mass and strength by adipose tissue.

Adipose tissue secretes numerous cytokines (termed ‘adipokines’) that have known or hypothesized actions on skeletal muscle. The majority of adipokines have been implicated in the pathological link between excess adipose and muscle insulin resistance, but approximately half also have documented in vitro effects on myogenesis and/or hypertrophy. This complexity suggests a potential dual role for adipokines in the regulation of muscle mass in homeostasis and the development of pathology. In this study, we used lipodystrophic ‘fat‐free’ mice to demonstrate that adipose tissue is indeed necessary for the development of normal muscle mass and strength. Fat‐free mice had significantly reduced mass (∼15%) and peak contractile tension (∼20%) of fast‐twitch muscles, a slowing of contractile dynamics and decreased cross‐sectional area of fast twitch fibres compared to wild‐type littermates. These deficits in mass and contractile tension were fully rescued by reconstitution of ∼10% of normal adipose mass, indicating that this phenotype is the direct consequence of absent adipose. We then showed that the rescue is solely mediated by the adipokine leptin, as similar reconstitution of adipose from leptin‐knockout mice fails to rescue mass or strength. Together, these data indicate that the development of muscle mass and strength in wild‐type mice is dependent on adipose‐secreted leptin. This finding extends our current understanding of the multiple roles of adipokines in physiology as well as disease pathophysiology to include a critical role for the adipokine leptin in muscle homeostasis. Key points Adipose‐derived cytokines (adipokines) have long been implicated in the pathogenesis of insulin resistance in obesity but likely have other under‐appreciated roles in muscle physiology.Here we use a fat‐free mouse to show that adipose tissue is necessary for the normal development of muscle mass and strength.Through add‐back of genetically modified adipose tissue we show that leptin is the key adipokine mediating this regulation.This expands our understanding of leptin's role in adipose–muscle signalling to include development and homeostasis and adds the surprising finding that leptin is the sole mediator of the maintenance of muscle mass and strength by adipose tissue.

Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue

ObjectivesTirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies focused on understanding how tirzepatide achieves its therapeutic efficacy. Recently, we found that treatment with tirzepatide improves insulin sensitivity in humans with T2D and obese mice in concert with a reduction in circulating levels of branched-chain amino (BCAAs) and keto (BCKAs) acids, metabolites associated with development of systemic insulin resistance (IR) and T2D. Importantly, these systemic effects were found to be coupled to increased expression of BCAA catabolic genes in thermogenic brown adipose tissue (BAT) in mice. These findings led us to hypothesize that tirzepatide may lower circulating BCAAs/BCKAs by promoting their catabolism in BAT. MethodsTo address this question, we utilized a murine model of diet-induced obesity and employed stable-isotope tracer studies in combination with metabolomic analyses in BAT and other tissues. ResultsTreatment with tirzepatide stimulated catabolism of BCAAs/BCKAs in BAT, as demonstrated by increased labeling of BCKA-derived metabolites, and increases in levels of byproducts of BCAA breakdown, including glutamate, alanine, and 3-hydroxyisobutyric acid (3-HIB). Further, chronic administration of tirzepatide increased levels of multiple amino acids in BAT that have previously been shown to be elevated in response to cold exposure. Finally, chronic treatment with tirzepatide led to a substantial increase in several TCA cycle intermediates (α-ketoglutarate, fumarate, and malate) in BAT. ConclusionsThese findings suggest that tirzepatide induces a thermogenic-like amino acid profile in BAT, an effect that may account for reduced systemic levels of BCAAs in obese IR mice.

Insulin Resistance and Other Comorbidities of Obesity as Independent Variables on Ventricular Repolarization in Children and Adolescents

Background: Obesity, a rapidly increasing global health problem in all age groups, is accepted as the basis for many chronic diseases through insulin resistance mechanism. This study aimed to examine whether insulin resistance and other comorbidities of obesity have an effect on the cardiac conduction system.&#x0D; Methods: The study included 50 obese and 47 healthy individuals aged 6–18 years. ECGs of all cases were taken; ECG waves and intervals were measured manually.&#x0D; Results: Of the obese group, 19 were boys (38%) and 31 were girls (62%), 27 were children (54%) and 23 were adolescents (46%), their ages were 11.3 ± 3.5 years. These particular characteristics were similar compared to the control group. However, in the obese group, the ECG parameters QTc (p = 0.001), QTd (p &lt; 0.001), QTdc (p &lt; 0.001), JTc (p &lt; 0.001), Tp-e (p &lt; 0.001), Tp-e/QT (p &lt; 0.001), Tp-e/QTc (p &lt; 0.001), Tp-e/JT (p &lt; 0.001), and Tp-e/JTc (p &lt; 0.001) were significantly longer. Twenty-five obese subjects (50%) had insulin resistance, when ECG parameters are compared to those without it, only JTc was significantly longer (332.3 ± 16.5 vs 321.7 ± 17.7 ms, p = 0.033). JTc duration mostly affected JT (p &lt; 0.001) and QTc (p &lt; 0.001). The 327 ms cut-off value of JTc indicated insulin resistance in the obese patients (p = 0.044) (sensitivity 60%, specificity 60%).&#x0D; Conclusion: Insulin resistance and other comorbidities of obesity may cause ventricular repolarization abnormalities at an early age. JTc, an ECG parameter, can be a guide in assessing ventricular repolarization abnormality and the risk of arrhythmia in these patients.&#x0D; Keywords: obesity, insulin resistance, comorbidities, ventricular repolarization, child, adolescence

The regulation of efferocytosis signaling pathways and adipose tissue homeostasis in physiological conditions and obesity: Current understanding and treatment options.

Obesity is associated with changes in the resolution of acute inflammation that contribute to the clinical complications. The exact mechanisms underlying unresolved inflammation in obesity are not fully understood. Adipocyte death leads to pro-inflammatory adipose tissue macrophages, stimulating additional adipocyte apoptosis. Thus, a complex and tightly regulated process to inhibit inflammation and maintain homeostasis after adipocyte apoptosis is needed to maintain health. In normal condition, a specialized phagocytic process (efferocytosis) performs this function, clearing necrotic and apoptotic cells (ACs) and controlling inflammation. For efficient and continued efferocytosis, phagocytes must internalize multiple ACs in physiological conditions and handle the excess metabolic burden in adipose tissue. In obesity, this control is lost and can be an important hallmark of the disease. In this regard, the deficiency of efferocytosis leads to delayed resolution of acute inflammation and can result in ongoing inflammation, immune system dysfunction, and insulin resistance in obesity. Hence, efficient clearance of ACs by M2 macrophages could limit long-term inflammation and ensue clinical complications, such as cardiovascular disease and diabetes. This review elaborates upon the molecular mechanisms to identify efferocytosis regulators in obesity, and the mechanisms that can improve efferocytosis and reduce obesity-related complications, such as the use of pharmacological agents and regular exercise.

1405-P: Bacteroides thetaiotaomicron Fortifies the Gut Mucosa and Improves Host Metabolism in Dietary Obese Mice

Disruption of the intestinal mucosa contributes to insulin resistance in obesity and Type 2 diabetes. Probiotic supplementation, which restores gut microbiota composition and fortifies intestinal barrier function, has therapeutic potential to treat obesity and metabolic disease. Treatment of mice on a chow diet or high fat diet (HFD) with Palmitic Acid Hydroxystearic Acids (PAHSAs) improves insulin sensitivity. These effects are mediated, at least in part, by changes in the gut microbiome. We used this paradigm to identify new microbes that may have beneficial metabolic effects. Metagenome sequencing of the cecum from mice treated with PAHSAs identified Bacteroides thetaiotaomicron (Bt) to be most strongly associated with insulin sensitivity. Here, we aimed to determine whether Bt supplementation in mice on a HFD diet has beneficial effects on energy balance and/or glucose homeostasis. Daily oral Bt supplementation in female mice fed a HFD resulted in less weight gain, lower adiposity, and improved glucose tolerance compared to vehicle-treated mice. Additionally, Bt supplementation preserved colonic mucus thickness, an indicator of gut health; increased the number of Goblet cells which are the cells that secrete mucin2, the predominant mucus protein that forms the intestinal mucosal barrier; and increased protein levels of mucin2 in the distal gut compared to vehicle-treated controls. These improvements in distal gut barrier architecture were associated with a reduction in circulating levels of pro-inflammatory lipopolysaccharide (LPS) and interleukin-6 (IL-6) . These beneficial effects of Bt were observed in female and not in male HFD-fed mice. These studies indicate that Bt has sex-specific effects to improve host metabolism in the setting of dietary obesity. Bt represents a next-generation probiotic and novel gut-based therapeutic strategy which could improve metabolic health in women. Disclosure J.Lee: None. K.Wellenstein: None. B.B.Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc., Consultant; Mellicell, Other Relationship; Alnylam Pharmaceuticals, Inc. Funding NIH KDK114162; JPB Foundation

217-LB: Hepatic Mig6 Ablation Restores Glucose Homeostasis during Diet-Induced Obesity and Aging

Hepatic epidermal growth factor receptor (EGFR) expression and activation are decreased during steatosis in humans and animal models of obesity. Restoring EGFR activation in obesity-induced endoplasmic reticulum (ER) stress and diabetes is a potential therapy to improve liver function and metabolism in type 2 diabetes (T2D) . Mitogen-inducible gene 6 (Mig6) is an inducible feedback inhibitor of EGFR activity; we previously observed that liver Mig6 expression was increased during obesity-induced insulin resistance in mice and by both pharmacological- and fatty acid-driven ER stress in hepatocytes, leading to decreased EGF-mediated EGFR activation. To test Mig6 as a potential target to treat insulin resistance in T2D, we examined liver-specific Mig6 knockout mice (LKO) and their littermate controls (CON) . LKO mice exhibited reduced liver fat content and normalized glycogen storage with diet-induced obesity. In addition, we observed enhanced hepatic insulin action and whole-body glucose tolerance, due to increased hepatic glucose uptake, as determined by hyperinsulinemic-euglycemic clamps. Using whole transcriptome sequencing, peroxisomal and mitochondrial beta-oxidation genes were decreased by Mig6 ablation, correlating with a compromised gene expression of liver gluconeogenic enzymes. Moreover, analysis of mice aged for one year, a different physiological insult causing insulin resistance and liver oxidative stress, we were able to recapitulate the main findings as with diet-induced obesity: decreased gluconeogenesis, enhanced liver glucose uptake leading to increased glucose tolerance. Moreover, in aged LKO mice, liver oxidative stress markers were reduced. In conclusion, we postulate that hepatic Mig6 deficiency partially reverts the effects of diabetes by decreasing hepatic glucose output and reducing cellular oxidative stress, thereby establishing Mig6 as a therapeutic candidate for treating insulin resistance in obesity and T2D. Disclosure J. M. Irimia-dominguez: None. E. A. Bloom-saldana: None. P. T. Fueger: Consultant; Protomer Technologies.