E4orf1 improves adipose tissue-specific metabolic risk factors and indicators of cognition function in a mouse model of Alzheimer's 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.

Potential contributors to variation in weight-loss response to liraglutide.

Obesity treatment requires a chronic state of negative energy balance. Obesity medications can help with this, increasing long-term dietary compliance by promoting satiety or reducing hunger. However, efficacy and safety of obesity medications vary for individuals. Early identification of non-responders to obesity medications may limit drug exposure while optimizing benefits for responders. This review summarizes factors that impact weight-loss response to liraglutide. Factors linked to greater weight loss on liraglutide include being female, not having diabetes, having relatively high baseline weight, and losing at least 4% of initial weight after 16 weeks of treatment. Other covariates that may predict treatment response but require further confirmation include central effects, nausea, gastric emptying of solids, and genotype. Baseline body mass index, race, and age seem less relevant for predicting weight-loss response to liraglutide. Lesser known and harder-to-measure factors such as cerebral blood flow, food cue reactivity, gut hormone levels, and dietary adherence possibly impact variability of response to liraglutide. This information should assist healthcare providers with establishing realistic weight-loss probability for individual patients. Future research should improve the ability to identify responders to liraglutide. Importantly, this review may provide a framework to identify responders to other obesity medications.

Greater protein quality of an egg breakfast may be inadequate to induce satiety during weight loss, compared with a cereal breakfast of equal protein quantity.

We compared the effects of consuming egg-breakfast of superior protein quality to cereal-breakfast of similar energy density and protein quantity, but lower protein quality. Two, two-week randomised crossover clinical trials included 30 otherwise healthy women with overweight or obesity. Subjects received counselling to follow a reduced-calorie diet. Under supervision, participants consumed either breakfast for one-week then crossed over to the opposite breakfast. Experiment-1 outcome variables included post-breakfast appetite hormones, glucose and insulin, subjective markers of satiety and energy intake at lunch and dinner. In Experiment-2, an appealing food (brownies) was included in lunch. Following the breakfasts, Experiment-1 showed no significant differences in outcome variables. In Experiment-2, the egg-breakfast increased fullness (p = 0.038), but lunch-time energy intake was not different. If these findings apply to other breakfasts, it suggests that in comparing two breakfasts with similar protein quantity, the greater protein quality of a breakfast may not be adequate to induce satiety.

E4orf1 Prevents Progression of Fatty Liver Disease in Mice on High Fat Diet.

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.

E4orf1-induced reduction in endogenous insulin level is independent of pancreas endocrine function.

BACKGROUND: Obesity is often associated with hyperinsulinemia due to insulin resistance. In mice models of hyperinsulinemia, adenovirus-derived E4orf1 protein promotes glucose disposal via insulin-independent pathway, and reduces insulin response to glucose load, described as its "Insulin Sparing Action". This is likely because less insulin is needed for disposing glucose in presence of E4orf1, however, there are other potential possibilities. This study determined if E4orf1 reduces insulin response to glucose load because it a) suppresses the ability of pancreatic ß-cells to secret insulin, or b) upregulates glucagon production by the pancreas. METHODS: C57BL/6J wild type (control) and transgenic C57BL/6J (E4orf1) mice that express E4orf1 protein in adipose tissue upon doxycycline feeding, were used. Post-doxycycline feeding, insulin and glucagon secretion in response to glibenclamide or phenylephrine were compared between the two groups. The pancreases were examined for histological changes. RESULTS: In response to glibenclamide, E4orf1 mice secreted more insulin and exhibited lower blood glucose compared to control (47.4 ± 4.4 vs 27.4 ± 3.7 mg/dl, p < 0.003), but showed no difference in glucagon secretion. Post-phenylephrine injection, no differences were observed between the two groups for glucagon or insulin, except E4orf1 mice had a lower blood glucose rise after 10-min of injection compared to the control (39.7 ± 4.7 vs. 58.3 ± 7.5 mg/dl, p < 0.05). E4orf1 mice had significantly larger pancreatic islets and higher number of islets per mm2 tissue area. Neither the size nor the number of islets met the criteria of hypertrophy or hyperplasia. CONCLUSIONS/INTERPRETATION: E4orf1 retains and may enhance the ability of the pancreases to secret insulin in response to insulin secretagogue. Glucagon does not seem to play a role in the Insulin Sparing Action of E4orf1. Overall, the histology studies support better pancreatic islet health in presence of E4orf1, compared to that in control mice. The "insulin-independent" role of E4orf1 has potential therapeutic implications in addressing hyperinsulinemia in obesity.

Egg and saturated fat containing breakfasts have no acute effect on acute glycemic control in healthy adults: a randomized partial crossover trial.

BACKGROUND/OBJECTIVES: High egg consumption is associated with poor glycemic control. Considering the widespread consumption of eggs, it is crucial to determine causality in this association. We tested if egg consumption acutely alters glucose disposal in the absence or presence of saturated fat, which is frequently consumed with eggs. SUBJECTS/METHODS: In a randomized partial crossover clinical trial, 48 subjects (consuming ≥ 1 egg/week) received two of four isocaloric, macronutrient-matched breakfasts. The groups were defined based on the main ingredient of the breakfasts offered: eggs (EB); saturated fat (SB); eggs and saturated fat (ES); and control, which included a cereal based breakfast (CB). The breakfasts were offered in two testing sessions spaced seven days apart. Six blood samples (pre breakfast (fasting); 30, 60, 90, 120, and 180 minutes post breakfast) were collected to measure glucose and insulin levels. Area under the curves (AUC) were analyzed controlling for the baseline concentrations using mixed-effects models accounting for within-subject dependencies to compare these across breakfast assignments. RESULTS: Forty-eight patients (46% males, age 25.8 ± 7.7 years, BMI 25.7 ± 4.6 kg/m2) were included. Neither EB, SB nor ES was associated with a significant difference in AUC of glucose or insulin compared to CB (p > 0.1). CONCLUSIONS: Acutely, consumption of egg breakfast with or without accompanying saturated fat does not adversely affect glucose disposal in healthy adults. While this is reassuring for continued egg consumption, a long-term evaluation of egg intake with or without saturated fat would be the next step.

Key Causes and Contributors of Obesity: A Perspective.

Obesity is a disease with several potential causes and contributors. This article provides a focused overview of key known causes of obesity and factors that contribute to obesity. Obesity ultimately results from impaired energy storage mechanisms, such as dysregulation of hunger, satiety, digestion, fat storage, and metabolic rate. In addition, myriad contributors promote its expression, including dietary factors, sleep quality and duration, psychological health and well-being, and tobacco cessation, among others. This article concludes with a discussion of the clinical relevance of causes and contributors in obesity prevention and treatment, which is paramount to providing effective, individualized clinical management.

Adenovirus 36 infection and daycare starting age are associated with adiposity in children and adolescents

Abstract Objective This study aimed to investigate human adenovirus 36 (Adv36) as an associated factor for adiposity in children and adolescents aged 9-12 years. Methods This was a case-control study comparing overweight (cases) and eutrophic (controls) children and adolescents aged 9-12 years based on their body mass index in relation to human adenovirus 36 serology. Human adenovirus 36-specific neutralizing antibodies were assessed using the serum neutralization assay, and a questionnaire regarding the subjects' personal backgrounds, breastfeed history, age of starting daycare, and eating and exercise habits was also applied. Results A total of 101 (51, eutrophic; 50, overweight) children were included in the study. The Adv36 seropositivity rate was of 15.8%, which increased the chance of being overweight by 3.17 times (p = 0.049). Enrollment in a full-time daycare center before the age of 24 months increased the chance of being overweight by 2.78 times (p = 0.027). Metabolic parameters (total cholesterol and blood glucose) were insignificantly different among children who were seropositive or seronegative for human adenovirus 36. Conclusion This study concluded that excessive weight was positively associated with seropositivity for human adenovirus 36. Early enrollment in a full-time daycare was also an associated factor for obesity. Such data, confirmed in new studies, reinforces the role of human adenovirus 36 in the increase of childhood adiposity.

Antidiabetic E4orf1 protein prevents hepatic steatosis and reduces markers of aging-related cellular damage in high fat fed older mice.

INTRODUCTION: Older age is associated with greater prevalence of hyperinsulinemia, type 2 diabetes, and fatty liver disease. These metabolic conditions and aging are bidirectionally linked to mitochondrial dysfunction and telomere attrition. Although effectively addressing these conditions is important for influencing the health and the lifespan, it is particularly challenging in older age. We reported that E4orf1, a protein derived from human adenovirus Ad36, reduces hyperinsulinemia, improves glucose clearance, and protects against hepatic steatosis in younger mice exposed to high fat diet (HFD). Here, we tested if E4orf1 will improve glycemic control, liver fat accumulation, mitochondrial integrity, and reduce telomere attrition in older mice. RESEARCH DESIGN AND METHODS: We used 9-month-old mice that inducibly expressed E4orf1 in adipose tissue and non-E4orf1 expressing control mice. Mice were maintained on a 60% (kcal) HFD for 20 weeks and glycemic control was determined by intraperitoneal glucose tolerance test at week 20. Following 20 weeks of HF-feeding, mice were sacrificed and liver tissues collected to determine the expression of aging genes using qRT-PCR based RT2 Profiler PCR array. RESULTS: Compared with the control mice, E4orf1 significantly improved glycemic control and reduced hepatic steatosis and fibrosis. Additionally, E4orf1 maintained markers of mitochondrial integrity and telomere attrition. CONCLUSION: E4orf1 has the potential to improve glycemic control in older mice, and the improvement persists even after longer term exposure. E4orf1 expression also maintains mitochondrial integrity and telomere attrition, thus delaying age-associated diseases. This provides strong evidence for therapeutic utility of E4orf1 in improving age-associated metabolic and cellular changes that occur with aging in humans.

The triumvirate: why hypertension, obesity, and diabetes are risk factors for adverse effects in patients with COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. The cellular receptor for SARS-CoV-2 entry is the angiotensin-converting enzyme 2, a membrane-bound homolog of angiotensin-converting enzyme. Henceforth, this has brought the attention of the scientific community to study the interaction between COVID-19 and the renin-angiotensin system (RAS), as well as RAS inhibitors. However, these inhibitors are commonly used to treat hypertension, chronic kidney disorder, and diabetes. Obesity is a known risk factor for heart disease, diabetes, and hypertension, whereas diabetes and hypertension may be indirectly related to each other through the effects of obesity. Furthermore, people with hypertension, obesity, diabetes, and other related complications like cardiovascular and kidney diseases have a higher risk of severe COVID-19 infection than the general population and usually exhibit poor prognosis. This severity could be due to systemic inflammation and compromised immune response and RAS associated with these comorbid conditions. Therefore, there is an urgent need to develop evidence-based treatment methods that do not affect the severity of COVID-19 infection and effectively manage these chronic diseases in people with COVID-19.

No association between consumption of eggs with energy or macronutrient intake: Objective evidence from the remote food photography method.

BACKGROUND AND AIMS: Greater egg consumption is associated with poor glycemic control. However, greater egg intake could simply be a marker for other dietary indiscretions such as greater intake of energy or saturated fat, which may influence glycemic control. We examined the association between egg consumption and total energy intake and saturated fat intake, measured using the remote food photography method. METHODS: An observational study was conducted with 48 healthy adults consuming ≥1 eggs/week. Photographs of all meals consumed for seven days were captured via a smartphone application called SmartIntake® and analyzed for nutrient intake. Fasting blood samples were collected. Linear correlations between egg consumption and nutrient intake or measures of glycemic control were determined. RESULTS: Daily egg intake was significantly associated with cholesterol intake, but not with the daily energy and saturated fat intake or measures of glycemic control. CONCLUSIONS: Higher consumption of eggs in free-living conditions was not associated with undesirable profiles of macronutrient intake, total EI, or an impaired glycemic profile in this study population. Thus, the assertion that eggs are linked with impaired glycemic control because of the accompanying intake of greater energy and saturated fat, does not appear valid. TRIAL REGISTRATION: NCT03404700.

Improvement in Glycemic Control in Mice of Different Age Groups.

AIMS AND METHODS: The declining ability to control blood glucose with advancement of age is an important health risk factor and may lead to insulin resistance, type-2-diabetes and Alzheimer's disease. Adenovirus 36(Ad36) improves glycemic control independent of insulin signaling(insulin sparing effect) as evidenced by cell, animal and observational human studies. This property of Ad36 may be useful in correcting aging-related glucose intolerance and related health conditions. Therefore, we determined the effect of Ad36 on glycemic control in older mice, to identify the age group that best responds to Ad36. Six, 12 or 20-month old C57Bl/6 mice on chow diet were each divided into weight-matched groups(mock-infected or Ad36-infected). Body weight was recorded weekly post infection (p.i.) and fasting glucose measured(week 0, 4, 8 and 20 p.i.). Blood glucose and serum insulin were measured during glucose tolerance test(week 0 and 16 p.i.). At week 20 p.i., animals were sacrificed, blood and tissues collected. RESULTS: Mice from all age groups showed improvement in glucose clearance post Ad36 infection, but a more profound effect was observed in 6-month old mice compared with mock-infected mice. Under fed conditions though there was no difference in blood glucose at 20 wk p.i., interestingly, Ad36 reduced serum insulin in age groups old mice, compared with control mice. CONCLUSIONS: These findings suggest Ad36 infected animals improve glycemic control and clear post-prandial gluco00000se increase without increasing insulin secretion in an insulin sparing manner. These beneficial effects provide strong evidence for developing Ad36-based approaches as a novel tool to attenuate age associated glucose intolerance.

E4orf1, an Adeno-viral protein, attenuates renal lipid accumulation in high fat fed mice: A novel approach to reduce a key risk factor for chronic kidney disease.

Obesity and hyperlipidemia are independent risk factors of chronic kidney disease (CKD). In mice, diet induced obesity accelerates lipogenesis, lipid accumulation, and injury in kidneys. Expression of adenoviral protein, E4orf1, improves glucose clearance and reduces endogenous insulin secretion to glucose challenge in mice. Therefore, in this pilot study, we examined, if enhanced glycemic control in HFD fed E4orf1 transgenic (E4orf1-Tg) mice, will reduce renal lipogenesis and lipid accumulation. In two separate experiments, E4orf1-Tg mice were fed 60% (kcal) high-fat diet (HFD) supplemented with doxycycline for 10-weeks or 20-weeks along with wild-type (C57BL6/J) or E4orf1-non-transgenic (E4orf1-non-Tg) control mice, respectively. Protein expression of Fatty Acid Synthase (FAS) and Acetyl-CoA Carboxylase (ACC), accumulation of triglyceride (TG) along with mRNA levels of lipid metabolism and injury markers were determined in kidneys. Renal expression of FAS and ACC, and TG content was significantly reduced in E4orf1-Tg mice compared to controls. E4orf1-Tg mice show significant increase in genes involved in mitochondrial fatty acid oxidation and oxidative stress compared to wild-type mice after 10-weeks of HFD. However, mice exposed to 20-weeks of HFD, show no difference in gene expression. E4orf1 expression reduces lipid synthesis and accumulation in kidneys despite HFD, which may be due to attenuation of hyperinsulinemia by E4orf1.