Autophagy and metabolic homeostasis: Exploration in obesity-related metabolic diseases (Review)

Adipose tissue develops lipids, aberrant adipokines, chemokines, and pro-inflammatory cytokines as a consequence of the low-grade systemic inflammation that characterizes obesity. This low-grade systemic inflammation can lead to insulin resistance (IR) and metabolic complications, such as type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Although the CXC chemokines consists of numerous regulators of inflammation, cellular function, and cellular migration, it is still unknown that how CXC chemokines and chemokine receptors contribute to the development of metabolic diseases (such as T2D and NAFLD) during obesity. In light of recent research, the objective of this review is to provide an update on the linkage between the CXC chemokine, obesity, and obesity-related metabolic diseases (T2D and NAFLD). We explore the differential migratory and immunomodulatory potential of CXC chemokines and their mechanisms of action to better understand their role in clinical and laboratory contexts. Besides that, because CXC chemokine profiling is strongly linked to leukocyte recruitment, macrophage recruitment, and immunomodulatory potential, we hypothesize that it could be used to predict the therapeutic potential for obesity and obesity-related diseases (T2D and NAFLD).

Obesity represents one of the major public health issues threatening the global health and promoting chronic metabolic disorders, including type 2 diabetes, insulin resistance (IR), hyperlipidemia, hypertension, polycystic ovary syndrome, metabolic-associated fatty liver disease (MAFLD), and others. Ferroptosis, a novel form of cell death, is a programmed cell death induced by iron-dependent lipid peroxidation. It is characterized by excessive iron accumulation and unregulated lipid peroxidation. The activity of ferroptosis is modulated by multiple factors such as iron, reactive oxygen species, and over 98 unsaturated fatty acids. Mounting evidence indicates that ferroptosis plays a crucial role in obesity-related chronic metabolic diseases like type 2 diabetes, IR, hyperlipidemia, hypertension, polycystic ovary syndrome, and MAFLD. Clarifying the molecular mechanism of ferroptosis may discover potential therapeutic targets for the treatment of these diseases. This article comprehensively reviews the role, pathogenesis, prevention, treatment strategies, current research gaps and future development directions of ferroptosis in obesity-related chronic metabolic diseases have been thoroughly discussed, and novel perspectives for the future treatment and research of ferroptosis in these diseases carefully provided. It points out directions for basic research on ferroptosis, raises urgent needs for developing precise intervention strategies, and provides new insights into the treatment and study of obesity-related chronic metabolic diseases in the future.

Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.

With the improvement of living conditions and the popularity of unhealthy eating and living habits, obesity is becoming a global epidemic. Obesity is now recognized as a disease that not only increases the risk of metabolic diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), and cancer but also negatively affects longevity and the quality of life. The traditional Chinese medicines (TCMs) are highly enriched in bioactive compounds and have been used for the treatment of obesity and obesity-related metabolic diseases over a long period of time. In this review, we selected the most commonly used anti-obesity or anti-hyperlipidemia TCMs and, where known, their major bioactive compounds. We then summarized their multi-target molecular mechanisms, specifically focusing on lipid metabolism, including the modulation of lipid absorption, reduction of lipid synthesis, and increase of lipid decomposition and lipid transportation, as well as the regulation of appetite. This review produces a current and comprehensive understanding of integrative and systematic mechanisms for the use of TCMs for anti-obesity. We also advocate taking advantage of TCMs as another therapy for interventions on obesity-related diseases, as well as stressing the fact that more is needed to be done, scientifically, to determine the active compounds and modes of action of the TCMs.

The spread of the Western lifestyle across the globe has led to a pandemic in obesity-related metabolic disease. The Mediterranean diet (MedDiet), Okinawa diet (OkD) and Nordic diet, derived from very different regions of the world and culinary traditions, have a large whole plant food component and are associated with reduced disease risk. This review focuses on polyphenol : microbiome interactions as one possible common mechanistic driver linking the protective effects whole plant foods against metabolic disease across healthy dietary patterns irrespective of geography. Although mechanistic evidence in humans is still scarce, animal studies suggest that polyphenol or polyphenol rich foods induce changes within the gut microbiota and its metabolic output of trimethylamine N-oxide, short-chain fatty acids, bile acids and small phenolic acids. These cross-kingdom signaling molecules regulate mammalian lipid and glucose homeostasis, inflammation and energy storage or thermogenesis, physiological processes determining obesity-related metabolic and cardiovascular disease risk. However, it appears that where in the intestine metabolites are produced, the microbiota communities involved, and interactions between the metabolites themselves, can all influence physiological responses, highlighting the need for a greater understanding of the kinetics and site of production of microbial metabolites within the gut. Interactions between polyphenols and metabolites produced by the gut microbiota are emerging as a possible unifying protective mechanism underpinning diverse healthy dietary patterns signaling across culinary traditions, across geography and across domains of life.

High sugar, high-fat diets and unhealthy lifestyles have led to an epidemic of obesity and obesity-related metabolic diseases, seriously placing a huge burden on socio-economic development. A deeper understanding and elucidation of the specific molecular biological mechanisms underlying the onset and development of obesity has become a key to the treatment of metabolic diseases. Recent studies have shown that the changes of bile acid composition are closely linked to the development of metabolic diseases. Bile acids can not only emulsify lipids in the intestine and promote lipid absorption, but also act as signaling molecules that play an indispensable role in regulating bile acid homeostasis, energy expenditure, glucose and lipid metabolism, immunity. Disorders of bile acid metabolism are therefore important risk factors for metabolic diseases. The farnesol X receptor, a member of the nuclear receptor family, is abundantly expressed in liver and intestinal tissues. Bile acids act as endogenous ligands for the farnesol X receptor, and erroneous FXR signaling triggered by bile acid dysregulation contributes to metabolic diseases, including obesity, non-alcoholic fatty liver disease and diabetes. Activation of FXR signaling can reduce lipogenesis and inhibit gluconeogenesis to alleviate metabolic diseases. It has been found that intestinal FXR can regulate hepatic FXR in an organ-wide manner. The crosstalk between intestinal FXR and hepatic FXR provides a new idea for the treatment of metabolic diseases. This review focuses on the relationship between bile acids and metabolic diseases and the current research progress to provide a theoretical basis for further research and clinical applications.

Healthy nutrition is essential for prevention of disease and for maintenance or promotion of health; although healthy nutrition remains to be precisely defined. Over the past several decades, various types of nutrients have been functionally validated and considered as critical components of healthy nutrition, which commonly include fiber-enriched carbohydrates, mono- or poly-unsaturated fatty acids, essential amino acids, and certain micronutrients. When managing obesity and obesity-associated metabolic diseases, much attention has been paid to the content of nutrients that is considered as healthy nutrition. Accumulating evidence also suggests that nutrient composition could be more important than the content of individual nutrients in the context of reducing body weight and obesity-associated risk for metabolic diseases. Consistently, it would be more important to focus on diet with differences in nutrient ratios rather than individual type(s) of nutrients in terms of managing obesity and metabolic diseases. In this review, recent advances in dietary management of obesity and obesity-related metabolic diseases have been discussed. This review also has highlighted several specific diet compositions and their differences in managing hypertension, type 2 diabetes, and non-alcoholic fatty liver disease.

Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.

Background: Nonalcoholic fatty liver disease (NAFLD) is thought to be the main driver for the recent rise of chronic liver disease and liver cancer. NAFLD is also associated with other obesity-related metabolic diseases. Relative fat deposition in the liver varies by race/ethnicity and may partially account for liver cancer disparities. Thus, we aimed to compare liver fat content across five racial/ethnic groups, assess their contribution to the metabolic syndrome (MetSx), and predict NAFLD using common blood biomarkers. Methods: We conducted a cross-sectional study within the Multiethnic Cohort. A total of 1,861 healthy men and women aged 60-77 years were recruited, after stratification on sex, ethnicity (African, Japanese, Latino, Native Hawaiian, or white ancestry), and six BMI categories (range, 17.1-49.8 kg/m2). We estimated total fat mass using DXA and liver fat content using abdominal MR imaging. Fasting blood was analyzed for ~50 markers including adipocytokines, insulin and IGFs, lipids and lipid-soluble micronutrients, liver enzymes, and steroid hormones, using multiple assay platforms. Liver fat amounts were compared across sex and ethnic groups after adjustment for age, total fat mass, and height. The contribution of liver fat to MetSx was estimated in multivariable-adjusted mediation analysis. A prediction model for NAFLD was developed using regularized logistic regression. Results: The correlation between liver fat and total fat was only moderate (rSp = 0.34) and varied across ethnic groups (0.20-0.55). Liver fat content was similar between the sexes but differed by ethnicity (p<.0001), with a four-fold range in NAFLD prevalence between Japanese Americans (57% in men, 72% in women) and African Americans (12%, 19%) after adjustment for total fat mass. Total fat-adjusted prevalence of MetSx also differed by ethnicity: compared to whites, it was higher among Japanese Americans and Native Hawaiian women and lower among African Americans and Latinos. This ethnic difference was significantly mediated by liver fat among African Americans (proportion mediated =19-24%), Japanese Americans (22-34%), and Native Hawaiian women (20%). The final prediction model for NAFLD included age, sex, BMI, waist circumference, waist/hip, and top five biomarker predictors (IGFBP2, HOMA-IR, TG, adiponectin, SHBG). Discrimination of NAFLD cases in a validation dataset had high accuracy (AUC=0.90), across ethnic groups (AUCs of 0.80-0.96), and was significantly improved by the biomarkers (p's for contrast<.0001, except in African Americans). Conclusions: Relative fat storage in the liver varies substantially by race/ethnicity. In particular, Japanese Americans and Native Hawaiian women appear to experience a greater metabolic burden from their propensity to store excess fat in ectopic areas, which is consistent with a stronger association of BMI with liver cancer in these groups. Key metabolism markers may be used to successfully detect and monitor NAFLD patients of in various ethnic groups. Citation Format: Unhee Lim, Lynne R. Wilkens, Kristine R. Monroe, Iona Cheng, Bruce S. Kristal, Johanna W. Lampe, Meredith A. Hullar, John Shepherd, Thomas Ernst, Loic Le Marchand. Racial/ethnic differences in liver fat, an obesity-associated risk factor for liver cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA38.

The prevalence of metabolic diseases, such as obesity, has been steadily increasing in recent years, posing a significant threat to public health. Therefore, early identification and intervention play a crucial role. With the deepening understanding of the etiology of metabolic diseases, novel therapeutic targets are emerging for the treatment of obesity, lipid metabolism disorders, cardiovascular and cerebrovascular diseases, glucose metabolism disorders, and other related metabolic conditions. IL-27, as a multi-potent cytokine, holds great promise as a potential candidate target in this regard. This article provides a comprehensive review of the latest findings on IL-27 expression and signal transduction in the regulation of immune inflammatory cells, as well as its implications in obesity and other related metabolic diseases. Furthermore, it explores the potential of IL-27 as a novel therapeutic target for the treatment of obesity and metabolic disorders. Finally, an overview is presented on both the opportunities and challenges associated with targeting IL-27 for therapeutic interventions.

Dysregulation along the gut microbiota-immune system axis after oral exposure to titanium dioxide nanoparticles: A possible environmental factor promoting obesity-related metabolic disorders

Background Neuregulin 4 (Nrg4) is a brown adipose tissue-derived adipokine that greatly affects systemic metabolism and improves metabolic derangements. Although abnormal circulating levels of Nrg4 are common in obesity, it remains elusive whether low or elevated levels of this batokine are associated with the onset of metabolic diseases. Aim To assess Nrg4 levels and its role as a feasible biomarker to predict the severity of obesity, gestational diabetes mellitus (GDM), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Methods A search for relevant studies was performed systematically using prominent search engines, including PubMed, Google Scholar, and Embase, by following PRISMA guidelines. Results Ample clinical evidence reported low serum/plasma levels of Nrg4 in obesity and these were inversely proportional to the indices of metabolic syndrome, including body mass index, waist circumference, triglycerides, fasting plasma glucose, and homoeostatic model assessment for insulin resistance as well as high-sensitivity C-reactive protein. Low circulating Nrg4 levels may aid in the prediction of morbid obesity, and subsequent GDM, T2DM, NAFLD, and CVD. Conclusion Current clinical evidence emphasizes that the circulating levels of Nrg4 are decreased in morbid obesity, and it also highlights that Nrg4 May serve as a potential prognostic biomarker for obesity-related metabolic diseases.

The advanced glycosylation end product receptor (RAGE) acts as a recognition receptor and interacts with different types of ligands that form and accumulate in the tissues and circulation, such as diabetes, inflammation, insulin resistance, and obesity. In these environments, RAGE is expressed on the surface of various cells associated with tissue disturbance. This review mainly summarizes the characteristics of RAGE-related signalling, with a particular emphasis on the role of RAGE in the development of obesity. We also briefly describe the phenotypes and characteristics of macrophages and focus on the role of adipose tissue macrophages (ATMs) and the regulatory mechanisms in obesity, diabetes, and other related metabolic diseases. Besides, we will also elaborate on the prospect of new strategies for treating diabetes and obesity-related metabolic diseases by inhibiting RAGE signalling and regulating ATMs recruitment and polarization.

Objective: To compare the efficacy and safety of laparoscopic single-anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S) and laparoscopic sleeve gastrectomy (SG) in the treatment of obesity and obesity-related metabolic diseases. Methods: A retrospective cohort study method was used to analyze the clinical data of 22 patients with obesity who underwent laparoscopic SADI-S in the China-Japan Union Hospital of Jilin university from May 2018 to December 2019 (SADI-S group). Meanwhile, 22 patients with obesity undergoing laparoscopic SG at the same period were selected in this study whose preoperative demographics, including sex, age, body weight, body mass index, metabolic diseases and blood index, were comparable to those of SADI-S group. All the patients were followed up at 3 months, 6 months and 12 months after operation to compare the weight loss [body weight, body mass index, percent of excess weight loss (%EWL) and percent of total weight loss (%TWL), etc.], remission of obesity-related metabolic diseases (hypertension, hyperuricemia, and type 2 diabetes mellitus, etc.) and nutritional deficiency (albumin, retinal-binding-protein, vitamin B12, vitamin D and iron protein, etc.) between the two groups. Results: All the patients successfully underwent laparoscopic bariatric surgery without conversion to laparotomy or death. Compared with SG group, SADI-S group had longer operative time [(204.8±38.3) minutes vs. (109.2±22.4) minutes, t=10.107, P<0.001], higher rate of intraoperative drainage tube [100.0% (22/22) vs. 50.0% (11/22), P<0.001], longer duration of indwelling drainage tube [4 (2-7) days vs. 1 (0-7) days, U=131.000, P=0.008], and the differences were statistically significant (all P<0.05). There was no significant difference between the SG group and the SADI-S group in terms of postoperative hospital stay and complication rate. The weight loss efficacy of SADI-S group and SG group was compared at 3, 6 and 12 months after operation. The results showed that with the increase of follow-up time, the patient's body weight and body mass index gradually decreased, %EWL and %TWL gradually increased (all P<0.05). There were no statistically significant differences in body weight, body mass index and %EWL between the SADI-S group and the SG group at 3, 6 and 12 months after operation (all P>0.05). There was no statistically significant difference of %TWL between two groups at 3 months after operation (F=0.846, P=0.368), but SADI-S group had higher %TWL at 6 and 12 months after operation and the differences were statistically significant (6-month: 34.0±5.1 vs. 30.2±4.3, F=5.813, P=0.025; 12-month: 42.9±6.8 vs. 34.8±7.6, F=14.262, P=0.001). Except for that the remission rate of total cholesterol of SADI-S group was higher than that of SG group, remission rates of metabolic diseases were not significantly different at different follow-up points (all P>0.05). As for the nutrient deficiency (albumin, retinal-binding-protein, iron protein, vitamin B12, vitamin D and folic acid) and the incidence of gallstones, no significant differences were found between two groups (all P>0.05). Conclusion: Both SADI-S and SG are safe and effective for the treatment of obesity and obesity-related metabolic diseases, but the former is more effective.

Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota?