Extent to which weight loss contributes to improving metabolic dysfunction-associated and metabolic and alcohol related/associated steatotic liver disease: a study on Japanese participants undergoing health checkups.

Introduction: The incidence of steatotic liver disease has increased in recent years. Thus, steatotic liver disease is a major public health issue in Japan. This study investigated the association between weight reduction and the remission of metabolic dysfunction-associated steatotic liver disease (MASLD)/Metabolic and alcohol related/associated liver disease (MetALD) in Japanese individuals undergoing health checkups. Methods: This retrospective observational study included 8,707 Japanese patients with MASLD/MetALD who underwent health checkups from May 2015 to March 2023. The participants were monitored for its remission at their subsequent visit. MASLD was diagnosed on abdominal ultrasonography and based on the presence of at least one of five metabolic abnormalities. The impact of body mass index (BMI) reduction on MASLD/MetALD remission was assessed via logistic regression analysis and using receiver operating characteristic curves. Results: Logistic regression analysis revealed that weight loss was significantly associated with MASLD/MetALD remission. Other factors including exercise habits and reduced alcohol consumption were significant predictors of MASLD/MetALD remission in the overall cohort and in male patients. The optimal BMI reduction cutoff values for MASLD/MetALD remission were 0.9 kg/m2 and 4.0% decrease in the overall cohort, 0.85 kg/m2 and 3.9% decrease in males, and 1.2 kg/m2 and 4.5% decrease in females. In participants with a BMI of 23 kg/m2, the cutoff values were 0.75 kg/m2 and 2.7% BMI reduction. Discussion: Weight reduction plays an important role in both MASLD and MetALD remission among Japanese individuals. That is, targeting specific BMI reduction is effective. This underscores the importance of targeted weight management strategies in preventing and managing MASLD/MetALD in the Japanese population.

Adipose Tissue Immunometabolism: Unveiling the Intersection of Metabolic and Immune Regulation.

UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).

Dietary Strategies in Postmenopausal Women with Chronic and Metabolic Diseases.

As women age, their nutritional needs change, governed by changes in hormones, level of physical activity, and dietary intake [...].

Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.

Circadian dysfunction and cardio-metabolic disorders in humans.

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.

The impact of a western diet on gut microbiota and circadian rhythm: A comprehensive systematic review of in vivo preclinical evidence.

AIMS: Here, we present a systematic review that compiles in vivo experimental data regarding the effect of the WD on the gut microbiota and its impact on the circadian rhythm. Additionally, we reviewed studies evaluating the combined effects of WD and circadian cycle disruption on gut microbiota and circadian cycle markers. MATERIALS AND METHODS: The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. KEY FINDINGS: Preclinical studies revealed that WD triggers circadian rhythmicity disruption, reduces the alpha-diversity of the microbiota and favors the growth of bacterial groups that are detrimental to intestinal homeostasis, such as Clostridaceae, Enterococcus, Parasutterella and Proteobacteria. When the WD is combined with circadian clock disruption, gut dysbiosis become more pronounced. Reduced cycling of Per3, Rev-erb and CLOCK in the intestine, which are related to dysregulation of lipid metabolism and potential metabolic disease, was observed. SIGNIFICANCE: In conclusion, current evidence supports the potential of WD to trigger microbiota dysregulation, disrupt the biological clock, and increase susceptibility to metabolic disorders and potentially chronic diseases.

Metabolic disorders exacerbate the formation of glial scar after stroke.

Metabolic disorders are risk factors for stroke exacerbating subsequent complications. Rapidly after brain injury, a glial scar forms, preventing excessive inflammation and limiting axonal regeneration. Despite the growing interest in wound healing following brain injury, the formation of a glial scar in the context of metabolic disorders is poorly documented. In this study, we used db/db mice to investigate the impact of metabolic perturbations on brain repair mechanisms, with a focus on glial scarring. First, we confirmed the development of obesity, poor glucose regulation, hyperglycaemia and liver steatosis in these mice. Then, we observed that 3 days after a 30-min middle cerebral artery occlusion (MCAO), db/db mice had larger infarct area compared with their control counterparts. We next investigated reactive gliosis and glial scar formation in db/+ and db/db mice. We demonstrated that astrogliosis and microgliosis were exacerbated 3 days after stroke in db/db mice. Furthermore, we also showed that the synthesis of extracellular matrix (ECM) proteins (i.e., chondroitin sulphate proteoglycan, collagen IV and tenascin C) was increased in db/db mice. Consequently, we demonstrated for the first time that metabolic disorders impair reactive gliosis post-stroke and increase ECM deposition. Given that the damage size is known to influence glial scar, this study now raises the question of the direct impact of hyperglycaemia/obesity on reactive gliosis and glia scar. It paves the way to promote the development of new therapies targeting glial scar formation to improve functional recovery after stroke in the context of metabolic disorders.

SMEK1 ablation promotes glucose uptake and improves obesity-related metabolic dysfunction via AMPK signaling pathway.

Obesity has become a major risk of global public health. SMEK1 is also known as a regulatory subunit of protein phosphatase 4 (PP4). Both PP4 and SMEK1 have been clarified in many metabolic functions, including the regulation of hepatic gluconeogenesis and glucose transporter gene expression in yeast. Whether SMEK1 participates in obesity and the broader metabolic role in mammals is unknown. Thus, we investigated the function of SMEK1 in white adipose tissue and glucose uptake. GWAS/GEPIA/GEO database was used to analyze the correlation between SMEK1 and metabolic phenotypes/lipid metabolism-related genes/obesity. Smek1 KO mice were generated to identify the role of SMEK1 in obesity and glucose homeostasis. Cell culture and differentiation of stromal-vascular fractions (SVFs) and 3T3-L1 were used to determine the mechanism. 2-NBDG was used to measure the glucose uptake. Compound C was used to confirm the role of AMPK. We elucidated that SMEK1 was correlated with obesity and adipogenesis. Smek1 deletion enhanced adipogenesis in both SVFs and 3T3-L1. Smek1 KO protected mice from obesity and had protective effects on metabolic disorders, including insulin resistance and inflammation. Smek1 KO mice had lower levels of fasting serum glucose. We found that SMEK1 ablation promoted glucose uptake by increasing p-AMPKα(T172) and the transcription of Glut4 when the effect on AMPK-regulated glucose uptake was due to the PP4 catalytic subunits (PPP4C). Our findings reveal a novel role of SMEK1 in obesity and glucose homeostasis, providing a potential new therapeutic target for obesity and metabolic dysfunction.NEW & NOTEWORTHY Our study clarified the relationship between SMEK1 and obesity for the first time and validated the conclusion in multiple ways by combining available data from public databases, human samples, and animal models. In addition, we clarified the role of SMEK1 in glucose uptake, providing an in-depth interpretation for the study of its function in glucose metabolism.

Understanding the Cardiovascular and Metabolic Health Effects of Air Pollution in the Context of Cumulative Exposomic Impacts.

Poor air quality accounts for more than 9 million deaths a year globally according to recent estimates. A large portion of these deaths are attributable to cardiovascular causes, with evidence indicating that air pollution may also play an important role in the genesis of key cardiometabolic risk factors. Air pollution is not experienced in isolation but is part of a complex system, influenced by a host of other external environmental exposures, and interacting with intrinsic biologic factors and susceptibility to ultimately determine cardiovascular and metabolic outcomes. Given that the same fossil fuel emission sources that cause climate change also result in air pollution, there is a need for robust approaches that can not only limit climate change but also eliminate air pollution health effects, with an emphasis of protecting the most susceptible but also targeting interventions at the most vulnerable populations. In this review, we summarize the current state of epidemiologic and mechanistic evidence underpinning the association of air pollution with cardiometabolic disease and how complex interactions with other exposures and individual characteristics may modify these associations. We identify gaps in the current literature and suggest emerging approaches for policy makers to holistically approach cardiometabolic health risk and impact assessment.

Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.

OBJECTIVE: Ketone bodies (such as ß-hydroxybutyrate or BHB) have been recently proposed as signals involved in brain regulation of energy homeostasis and obesity development. However, the precise role of ketone bodies sensing by the brain, and its impact on metabolic disorder development remains unclear. Nevertheless, partial deletion of the ubiquitous ketone bodies transporter MCT1 in mice (HE mice) results in diet-induced obesity resistance, while there is no alteration under normal chow diet. These results suggest that ketone bodies produced during the high fat diet would be important signals involved in obesity onset. METHODS: In the present study we used a specific BHB infusion of the hypothalamus and analyzed the energy homeostasis of WT or HE mice fed a normal chow diet. RESULTS: Our results indicate that high BHB levels sensed by the hypothalamus disrupt the brain regulation of energy homeostasis. This brain control dysregulation leads to peripheral alterations of energy expenditure mechanisms. CONCLUSIONS: Altogether, the changes induced by high ketone bodies levels sensed by the brain increase the risk of obesity onset in mice.

The complex landscape of intracellular signalling in protein modification under hyperglycaemic stress leading to metabolic disorders.

Hyperglycaemia is a life-threatening risk factor that occurs in both chronic and acute phases and has been linked to causing injury to many organs. Protein modification was triggered by hyperglycaemic stress, which resulted in pathogenic alterations such as impaired cellular function and tissue damage. Dysregulation in cellular function increases the condition associated with metabolic disorders, including cardiovascular diseases, nephropathy, retinopathy, and neuropathy. Hyperglycaemic stress also increases the proliferation of cancer cells. The major areas of experimental biomedical research have focused on the underlying mechanisms involved in the cellular signalling systems involved in diabetes-associated chronic hyperglycaemia. Reactive oxygen species and oxidative stress generated by hyperglycaemia modify many intracellular signalling pathways that result in insulin resistance and ß-cell function degradation. The dysregulation of post translational modification in ß cells is clinically associated with the development of diabetes mellitus and its associated diseases. This review will discuss the effect of hyperglycaemic stress on protein modification and the cellular signalling involved in it. The focus will be on the significant molecular changes associated with severe metabolic disorders.

Offspring cardiometabolic outcomes and postnatal growth trajectories after exposure to maternal SARS-CoV-2 infection.

OBJECTIVE: The objective of this study is to determine whether in utero exposure to SARS-CoV-2 is associated with increased risk for a cardiometabolic diagnosis by 18 months of age. METHODS: This retrospective electronic health record (EHR)-based cohort study included the live-born offspring of all individuals who delivered during the COVID-19 pandemic (April 1, 2020-December 31, 2021) at eight hospitals in Massachusetts. Offspring exposure was defined as a positive maternal SARS-CoV-2 polymerase chain reaction test during pregnancy. The primary outcome was presence of an ICD-10 code for a cardiometabolic disorder in offspring EHR by 18 months. Weight-, length-, and BMI-for-age z scores were calculated and compared at 6-month intervals from birth to 18 months. RESULTS: A total of 29,510 offspring (1599 exposed and 27,911 unexposed) were included. By 18 months, 6.7% of exposed and 4.4% of unexposed offspring had received a cardiometabolic diagnosis (crude odds ratio [OR] 1.47 [95% CI: 1.10 to 1.94], p = 0.007; adjusted OR 1.38 [1.06 to 1.77], p = 0.01). Exposed offspring had a significantly greater mean BMI-for-age z score versus unexposed offspring at 6 months (z score difference 0.19 [95% CI: 0.10 to 0.29], p < 0.001; adjusted difference 0.04 [-0.06 to 0.13], p = 0.4). CONCLUSIONS: Exposure to maternal SARS-CoV-2 infection was associated with an increased risk of receiving a cardiometabolic diagnosis by 18 months preceded by greater BMI-for-age at 6 months.

Maternal Phlorizin Intake Protects Offspring from Maternal Obesity-Induced Metabolic Disorders in Mice via Targeting Gut Microbiota to Activate the SCFA-GPR43 Pathway.

Maternal obesity increases the risk of obesity and metabolic disorders (MDs) in offspring, which can be mediated by the gut microbiota. Phlorizin (PHZ) can improve gut dysbiosis and positively affect host health; however, its transgenerational metabolic benefits remain largely unclear. This study aimed to investigate the potential of maternal PHZ intake in attenuating the adverse impacts of a maternal high-fat diet on obesity-related MDs in dams and offspring. The results showed that maternal PHZ reduced HFD-induced body weight gain and fat accumulation and improved glucose intolerance and abnormal lipid profiles in both dams and offspring. PHZ improved gut dysbiosis by promoting expansion of SCFA-producing bacteria, Akkermansia and Blautia, while inhibiting LPS-producing and pro-inflammatory bacteria, resulting in significantly increased fecal SCFAs, especially butyric acid, and reduced serum lipopolysaccharide levels and intestinal inflammation. PHZ also promoted intestinal GLP-1/2 secretion and intestinal development and enhanced gut barrier function by activating G protein-coupled receptor 43 (GPR43) in the offspring. Antibiotic-treated mice receiving FMT from PHZ-regulated offspring could attenuate MDs induced by receiving FMT from HFD offspring through the gut microbiota to activate the GPR43 pathway. It can be regarded as a promising functional food ingredient for preventing intergenerational transmission of MDs and breaking the obesity cycle.

Human gut microbiome: Therapeutic opportunities for metabolic syndrome-Hype or hope?

Shifts in gut microbiome composition and metabolic disorders are associated with one another. Clinical studies and experimental data suggest a causal relationship, making the gut microbiome an attractive therapeutic goal. Diet, intake of probiotics or prebiotics and faecal microbiome transplantation (FMT) are methods to alter a person's microbiome composition. Although FMT may allow establishing a proof of concept to use microbiome modulation to treat metabolic disorders, studies show mixed results regarding the effects on metabolic parameters as well as on the composition of the microbiome. This review summarizes the current knowledge on diet, probiotics, prebiotics and FMT to treat metabolic diseases, focusing on studies that also report alterations in microbiome composition. Furthermore, clinical trial results on the effects of common drugs used to treat metabolic diseases are synopsized to highlight the bidirectional relationship between the microbiome and metabolic diseases. In conclusion, there is clear evidence that microbiome modulation has the potential to influence metabolic diseases; however, it is not possible to distinguish which intervention is the most successful. In addition, a clear commitment from all stakeholders is necessary to move forward in the direction of developing targeted interventions for microbiome modulation.

Thermoneutral Housing Enables Studies of Vertical Transmission of Obesogenic Diet-Driven Metabolic Diseases.

Vertical transmission of obesity is a critical contributor to the unabated obesity pandemic and the associated surge in metabolic diseases. Existing experimental models insufficiently recapitulate "human-like" obesity phenotypes, limiting the discovery of how severe obesity in pregnancy instructs vertical transmission of obesity. Here, via utility of thermoneutral housing and obesogenic diet feeding coupled to syngeneic mating of WT obese female and lean male mice on a C57BL/6 background, we present a tractable, more "human-like" approach to specifically investigate how maternal obesity contributes to offspring health. Using this model, we found that maternal obesity decreased neonatal survival, increased offspring adiposity, and accelerated offspring predisposition to obesity and metabolic disease. We also show that severe maternal obesity was sufficient to skew offspring microbiome and create a proinflammatory gestational environment that correlated with inflammatory changes in the offspring in utero and adulthood. Analysis of a human birth cohort study of mothers with and without obesity and their infants was consistent with mouse study findings of maternal inflammation and offspring weight gain propensity. Together, our results show that dietary induction of obesity in female mice coupled to thermoneutral housing can be used for future mechanistic interrogations of obesity and metabolic disease in pregnancy and vertical transmission of pathogenic traits.

Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals.

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and ß-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases.

Purple Napiergrass (Pennisetum purpureum Schumach) Hot Water Extracts Ameliorate High-Fat Diet-Induced Obesity and Metabolic Disorders in Mice.

Purple Pennisetum (Pennisetum purpureum Schumach), a hybrid between Taihucao No. 2 and the local wild species of purple Pennisetum, has dark red stems and leaves due to its anthocyanin content. This study explores the potential of purple napiergrass extracts (PNE) in alleviating obesity and metabolic disorders induced by a high-fat diet in mice, where 50% of the caloric content is derived from fat. Mice were orally administered low-dose or high-dose PNE alongside a high-fat diet. Experimental findings indicate that PNE attenuated weight gain, reduced liver, and adipose tissue weight, and lowered blood cholesterol, triglyceride, low-density lipoprotein, and blood sugar levels. Stained sections showed that PNE inhibited lipid accumulation and fat hypertrophy in the liver. Immunoblotting analysis suggested that PNE improved the inflammatory response associated with obesity, dyslipidemia, and hyperglycemia induced by a high-fat diet. Furthermore, PNE potentially functions as a PPAR-γ agonist, increasing the adiponectin (ADIPOQ) concentration and suppressing inflammatory factors, while elevating the anti-inflammatory factor interleukin-10 (IL-10) in the liver. PNE-treated mice showed enhanced activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways and increased fatty acid oxidation and liver lipolysis. In conclusion, this study elucidated the mechanisms underlying the anti-inflammatory, PI3K/Akt, and AMPK pathways in a high-fat diet-induced obesity model. These findings highlight the potential of PNE in reducing weight, inhibiting inflammation, and improving blood sugar and lipid levels, showing the potential for addressing obesity-related metabolic disorders in humans.

[Russian eligibility criteria prescribing menopausal hormonal hormones therapy for patients with cardiovascular and metabolic diseases. Consensus document of the Russian Cardiological Society, Russian Society of Obstetricians and Gynecologists, Russian Association of Endocrinologists, Eurasian Association of Therapists, Association of Phlebologists of Russia].

Menopausal symptoms can disrupt the life course of women at the peak of their career and family life. Currently, the most effective treatment for these manifestations is menopausal hormone therapy (MHT). The presence of cardiovascular and metabolic diseases in itself does not exclude the possibility of prescribing MHT to relieve menopausal symptoms and improve quality of life. However, often an obstacle to the use of this type of hormonal therapy is the fear of doctors who are afraid of doing more harm to patients than good. Caution is especially important when it comes to women with underlying health conditions. Moreover, it should be recognized that there is a lack of high-quality research regarding the safety of MHT for major chronic non-infectious diseases and common comorbid conditions. The presented consensus document analyzed all currently available data obtained from clinical trials of various designs and created a set of criteria for the acceptability of prescribing MHT to women with concomitant cardiovascular and metabolic diseases. Based on the presented document, doctors of various specialties who advise women in menopause will receive an accessible algorithm that will allow them to avoid potentially dangerous situations and reasonably prescribe MHT in real practice.