Vijay Hegde

The rising prevalence of childhood obesity is closely linked to the early onset of comorbid conditions, notably metabolic dysfunction-associated steatotic liver disease (MASLD), a hepatic manifestation of metabolic syndrome characterized by hepatic steatosis in the absence of significant alcohol intake. The pathophysiology of MASLD includes complex interactions among various factors such as hormonal, genetic, lifestyle and nutritional, and environmental dynamics. Emerging evidence indicates that MASLD is independently associated with a higher risk of cardiovascular disease (CVD), irrespective of traditional CV-risk factors such as hypertension, dyslipidemia, and diabetes mellitus. A comprehensive, multipronged approach is central to the detection, monitoring, and management of MASLD and associated adverse cardiovascular outcomes in children. Currently, there are no approved medications or other specific therapies for pediatric MASLD. While early stages of the disease are potentially reversible through lifestyle modifications, including diet/nutrition and physical activity, these strategies are often difficult to implement and sustain over time. Early detection of progression of MASLD to more severe conditions is hampered by the lack of reliable noninvasive methods of risk assessment tools. The objective of this review is to (1) succinctly summarize the relationship between MASLD and CVD risk in children and (2) discuss advances in MASLD management and treatment in children. We believe that this article will stimulate new avenues for research into MASLD and its broader cardiometabolic implications in pediatric populations.

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by progressive cognitive decline due to the loss of neurons. The accumulation of extracellular senile plaques (Aβ) and intracellular tau neurofibrillary tangles (NFTs) is a key pathological feature of AD. Mitochondrial dysfunction is implicated in all key AD pathologies, whether as a cause or a consequence of disease progression. Growing evidence indicates that mitochondrial impairment plays a central role in AD pathogenesis by disrupting cellular homeostasis, promoting oxidative stress, and contributing to progressive neuronal death. Therefore, targeting mitochondria may offer promising insights into the development of disease-modifying therapies. In this review, we summarize current evidence on the role of mitochondrial dysfunction in the pathophysiology of AD and on its therapeutic potential.

Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major global health burden, ranking as the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The rising incidence of HCC is closely linked to metabolic comorbidities, including non-alcoholic fatty liver disease (NAFLD), underscoring the need for improved diagnostic and therapeutic strategies. NAFLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by inflammation and fibrosis, which markedly increases HCC risk, especially in individuals with obesity and type 2 diabetes (T2D). NAFLD has recently been redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) to better reflect its metabolic basis. However, robust experimental models to study the progression from MASLD to MASH and ultimately HCC remain limited. This proof-of-concept study investigates sex-specific effects of metabolic dysregulation using the STAM (STelic Animal Model; streptozotocin and high-fat diet) mouse model, which recapitulates key features of human MASH and HCC. Neonatal C57BL/6J mice received streptozotocin to induce T2D-like symptoms followed by a high-fat diet. Streptozotocin (STZ) treated mice showed reduced body fat, lower insulin levels, impaired glucose tolerance, and increased expression of genes linked to inflammation, lipid metabolism, and apoptosis. These findings support the STAM model’s utility for MASLD research and highlight the importance of sex-specific strategies to limit HCC progression.

Background Human adenovirus Ad36-derived protein, termed INSPARIN, up-regulates cellular glucose uptake through insulin-independent cell signaling. Transgenic or viral vector mediated delivery of INSPARIN exhibits significant anti-diabetic potential in mice. To translate these findings for clinical use, this preclinical study determined the short- and long-term effectiveness of nano-liposome-mediated delivery of INSPARIN to improve glucose metabolism in cell and animal models. Methods Void or INSPARIN Nanoparticles (NP) composed of soy-phosphatidylcholine were prepared freshly before use. Glucose uptake was measured in 3T3-L1, C2C12, and HepG2 cells following 72 h treatment with void or INSPARIN NP using a [³H]-2-deoxyglucose uptake assay. Male C57BL/6J mice fed a 45% high-fat diet received single or repeated subcutaneous injections of INSPARIN NP, followed by oral glucose tolerance tests, serum insulin, and HbA1c measurements. Biodistribution was assessed by DiD-labeled nanoparticle imaging, and long-term safety was evaluated by histopathology of major organs. Results INSPARIN NP upregulated glucose uptake in preadipocytes, hepatocytes, and myoblasts. In mice, INSPARIN NP delivered the drug to the liver when administered intravenously and to inguinal adipose tissue when administered subcutaneously. Single subcutaneous administration of INSPARIN NP promoted faster blood glucose clearance in a dose-dependent manner, but without leading to hypoglycemia. Daily subcutaneous administration of INSPARIN NP for seven weeks significantly reduced HbA1c levels despite continued high fat diet, and without any adverse effects on major organs studied. Conclusions These findings support suitability of nano-liposome mediated subcutaneous delivery of INSPARIN in clinical trials for treating diabetes.

Obesity results from a complex interplay between biological and environmental factors. The term “obesities” may more aptly describe its multifactorial etiology. Obesity increases susceptibility to microbial infection and may lead to poor outcomes. For example, patients with obesity have a poor prognosis and greater mortality following influenza or COVID-19 infection. Conversely, several viruses, bacteria, parasites, and scrapie agents can contribute to obesity. Among the adipogenic microbes, human adenovirus-36 (Ad36) is extensively investigated for its correlative or causative links with obesity in humans and animal models. Natural or experimental exposure to Ad36 is also linked with lower serum lipids and better glycemic control. The E4orf1 gene of Ad36 is responsible for improving glycemic control and shows strong therapeutic potential. Identifying the contributions of various pathogens in obesity may lead to effective treatment of subtypes of obesity through the development of respective vaccines or other treatments. Finally, for individuals suffering from the stigma of obesity, the possibility that a microbe can cause some types of obesity provides strong assurance that obesity is not a choice or a moral failure, but a serious disease.

Objective: Obesity, impaired glycemic control, and hepatic steatosis often coexist and are risk factors for developing dementia, and Alzheimer’s disease (AD). We hypothesized that a therapeutic agent that improves glycemic control and steatosis may attenuate obesity-associated progression of dementia. We previously identified that adenoviral protein E4orf1 improves glycemic control and reduces hepatic steatosis despite obesity in mice. Here, we determined if this metabolic improvement by E4orf1 will ameliorate cognitive decline in a transgenic mouse model of AD. Methods: Fourteen- to twenty-month-old APP/PS1/E4orf1 and APP/PS1 (control) mice were fed a high-fat diet. Cognition was determined by Morris Water Maze (MWM). Systemic glycemic control and metabolic signaling changes in adipose tissue, liver, and brain were determined. Results: Compared to control, E4orf1 expression significantly improved glucose clearance, reduced endogenous insulin requirement and lowered body-fat, enhanced glucose and lipid metabolism in adipose tissue, and reduced de novo lipogenesis in the liver. In the brain, E4orf1 mice displayed significantly greater expression of genes involved in neurogenesis and amyloid-beta degradation and performed better in MWM testing. Conclusion: This study opens-up the possibility of addressing glycemic control and steatosis for attenuating obesity-related cognitive decline. It also underscores the potential of E4orf1 for the purpose, which needs further investigations.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of function and eventual death of neurons in the brain. Multiple studies have highlighted the involvement of mitochondria in the initiation and advancement of neurodegenerative diseases. Mitochondria are essential for ATP generation, bioenergetics processes, the regulation of calcium homeostasis and free radical scavenging. Disrupting any of these processes has been acknowledged as a major contributor to the pathogenesis of common neurodegenerative diseases, especially AD. Several longitudinal studies have demonstrated type 2 diabetes (T2D) as a risk factor for the origin of dementia leading towards AD. Even though emerging research indicates that anti-diabetic intervention is a promising option for AD prevention and therapy, results from clinical trials with anti-diabetic agents have not been effective in AD. Interestingly, defective mitochondrial function has also been reported to contribute towards the onset of metabolic disorders including obesity and T2D. The most prevalent consequences of mitochondrial dysfunction include the generation of inflammatory molecules and reactive oxygen species (ROS), which promote the onset and development of metabolic impairment and neurodegenerative diseases. Current evidence indicates an association of impaired peripheral mitochondrial function with primary AD pathology; however, the mechanisms are still unknown. Therefore, in this review, we discuss if mitochondrial dysfunction-mediated metabolic disorders have a potential connection with AD development, then would addressing peripheral mitochondrial dysfunction have better therapeutic outcomes in preventing metabolic disorder-associated AD pathologies.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder with a complex pathophysiology. Type 2 diabetes (T2D) is a strong risk factor for AD that shares similar abnormal features including metabolic dysregulation and brain pathology such as amyloid and/or Tau deposits. Emerging evidence suggests that circulating branched-chain amino acids (BCAAs) are associated with T2D. While excess BCAAs are shown to be harmful to neurons, its connection to AD is poorly understood. Here we show that individuals with AD have elevated circulating BCAAs and their metabolites compared to healthy individuals, and that a BCAA metabolite is correlated with the severity of dementia. APP_Swe mouse model of AD also displayed higher plasma BCAAs compared to controls. In pursuit of understanding a potential causality, BCAA supplementation to HT-22 neurons was found to reduce genes critical for neuronal health while increasing phosphorylated Tau. Moreover, restricting BCAAs from diet delayed cognitive decline and lowered AD-related pathology in the cortex and hippocampus in APP/PS1 mice. BCAA restriction for two months was sufficient to correct glycemic control and increased/restored dopamine that were severely reduced in APP/PS1 controls. Treating 5xFAD mice that show early brain pathology with a BCAA-lowering compound recapitulated the beneficial effects of BCAA restriction on brain pathology and neurotransmitters including norepinephrine and serotonin. Collectively, this study reveals a positive association between circulating BCAAs and AD. Our findings suggest that BCAAs impair neuronal functions whereas BCAA-lowering alleviates AD-related pathology and cognitive decline, thus establishing a potential causal link between BCAAs and AD progression.

Non-alcoholic fatty liver disease (NAFLD) covers a broad spectrum of liver diseases ranging from steatosis to cirrhosis. There are limited data on prevention of hepatic steatosis or its progression to liver disease. Here, we tested if either transgenic (Tg) doxycycline-induced expression in adipose tissue of E4orf1 (E4), an adenoviral protein, or dietary fat restriction attenuated hepatic steatosis or its progression in mice. Twelve to fourteen-week-old TgE4 mice (E4 group) and control mice were exposed to a 60% (Kcal) high fat diet (HFD) for 20 weeks, while another group of mice on HFD for 10 weeks were switched to a chow diet (chow group) for another 10 weeks. Glycemic control was determined at weeks 10 and 20. Tissues were collected for gene and protein analysis at sacrifice. Compared to control, diet reversal significantly reduced body weight in the chow group, whereas E4 expression attenuated weight gain, despite HFD. E4 mice evinced significantly improved glucose clearance, lower endogenous insulin secretion, reduced serum triglycerides, attenuated hepatic steatosis and inflammation. Interestingly, in spite of weight loss and lower liver fat, chow mice showed significant upregulation of hepatic genes involved in lipid metabolism. Despite HFD, E4 prevents hepatic lipid accumulation and progression of hepatic steatosis, while diet reversal maintains hepatic health, but is unable to improve molecular changes.