Individuality and ethnicity eclipse a short-term dietary intervention in shaping microbiomes and viromes.

Many diseases linked with ethnic health disparities associate with changes in microbial communities in the United States, but the causes and persistence of ethnicity-associated microbiome variation are not understood. For instance, microbiome studies that strictly control for diet across ethnically diverse populations are lacking. Here, we performed multiomic profiling over a 9-day period that included a 4-day controlled vegetarian diet intervention in a defined geographic location across 36 healthy Black and White females of similar age, weight, habitual diets, and health status. We demonstrate that individuality and ethnicity account for roughly 70% to 88% and 2% to 10% of taxonomic variation, respectively, eclipsing the effects a short-term diet intervention in shaping gut and oral microbiomes and gut viromes. Persistent variation between ethnicities occurs for microbial and viral taxa and various metagenomic functions, including several gut KEGG orthologs, oral carbohydrate active enzyme categories, cluster of orthologous groups of proteins, and antibiotic-resistant gene categories. In contrast to the gut and oral microbiome data, the urine and plasma metabolites tend to decouple from ethnicity and more strongly associate with diet. These longitudinal, multiomic profiles paired with a dietary intervention illuminate previously unrecognized associations of ethnicity with metagenomic and viromic features across body sites and cohorts within a single geographic location, highlighting the importance of accounting for human microbiome variation in research, health determinants, and eventual therapies. Trial Registration: ClinicalTrials.gov ClinicalTrials.gov Identifier: NCT03314194.

Obesity Is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks. Next, carvedilol, a third-generation ß-blocker and a biased agonist that exhibits agonist-like effects through ß arrestins by activating extracellular signal-regulated kinase, was used to decrease one of these parameters, namely hypertension. Heart function was evaluated by invasive pressure-volume loops and echocardiography as well as by ex vivo working heart perfusions. Glycolysis and oxidation rates of glucose, fatty acids, and ketones were measured in the isolated working hearts. The development of HFpEF was associated with a dramatic decrease in cardiac glucose oxidation rates, with a parallel increase in palmitate oxidation rates. Carvedilol treatment decreased the development of HFpEF but had no major effect on cardiac energy substrate metabolism. Carvedilol treatment did increase the expression of cardiac ß arrestin 2 and proteins involved in mitochondrial biogenesis. Decreasing bodyweight in obese HFpEF mice increased glucose oxidation and improved heart function. This suggests that the dramatic energy metabolic changes in HFpEF mice hearts are primarily due to the obesity component of the HFpEF model. SIGNIFICANCE STATEMENT: Metabolic inflexibility occurs in heart failure with preserved ejection fraction (HFpEF) mice hearts. Lowering blood pressure improves heart function in HFpEF mice with no major effect on energy metabolism. Between hypertension and obesity, the latter appears to have the major role in HFpEF cardiac energetic changes. Carvedilol increases mitochondrial biogenesis and overall energy expenditure in HFpEF hearts.

Stimulating cardiac glucose oxidation lessens the severity of heart failure in aged female mice.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60% high-fat diet (HFD) with 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME) administered via drinking water to induce obesity and hypertension. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of myocardial glucose oxidation and fatty acid oxidation. Additionally, a series of mice subjected to the obesity and hypertension protocol were treated with a pyruvate dehydrogenase kinase inhibitor (PDKi) to stimulate cardiac glucose oxidation. Aged female mice subjected to the obesity and hypertension protocol had increased body weight, glucose intolerance, elevated blood pressure, cardiac hypertrophy, systolic dysfunction, and decreased survival. While fatty acid oxidation rates were not altered in the failing hearts, insulin-stimulated glucose oxidation rates were markedly impaired. PDKi treatment increased cardiac glucose oxidation in heart failure mice, which was accompanied with improved systolic function and decreased cardiac hypertrophy. The primary energy metabolic change in heart failure induced by obesity and hypertension in aged female mice is a dramatic decrease in glucose oxidation. Stimulating glucose oxidation can lessen the severity of heart failure and exert overall functional benefits.

The consumption of animal products is associated with plasma levels of alpha-aminoadipic acid (2-AAA).

BACKGROUND AND AIMS: The cardiometabolic disease-associated metabolite, alpha-aminoadipic acid (2-AAA) is formed from the breakdown of the essential dietary amino acid lysine. However, it was not known whether elevated plasma levels of 2-AAA are related to dietary nutrient intake. We aimed to determine whether diet is a determinant of circulating 2-AAA in healthy individuals, and whether 2-AAA is altered in response to dietary modification. METHODS AND RESULTS: We investigated the association between 2-AAA and dietary nutrient intake in a cross-sectional study of healthy individuals (N = 254). We then performed a randomized cross-over dietary intervention trial to investigate the effect of lysine supplementation (1 week) on 2-AAA in healthy individuals (N = 40). We further assessed the effect of a vegetarian diet on 2-AAA in a short-term (4-day) dietary intervention trial in healthy omnivorous women (N = 35). We found that self-reported dietary intake of animal products, including meat, poultry, and seafood, was associated with higher plasma 2-AAA cross-sectionally (P < 0.0001). Supplementary dietary lysine (5g/day) caused no significant increase in plasma 2-AAA; however, plasma 2-AAA was altered by general dietary modification. Further, plasma 2-AAA was significantly reduced by a short-term vegetarian diet (P = 0.003). CONCLUSION: We identified associations between plasma 2-AAA and consumption of animal products, which were validated in a vegetarian dietary intervention trial, but not in a trial designed to specifically increase the 2-AAA amino acid precursor lysine. Further studies are warranted to investigate whether implementation of a vegetarian diet improves cardiometabolic risk in individuals with elevated 2-AAA.

Effect of the glucagon-like peptide-1 receptor agonist liraglutide, compared to caloric restriction, on appetite, dietary intake, body fat distribution and cardiometabolic biomarkers: A randomized trial in adults with obesity and prediabetes.

AIMS: To investigate the hypothesis that weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, that also enhances GLP-1 activity - to determine the independent effects of each treatment. METHODS: A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (-390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg/d) as a weight-neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x-ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal-Wallis test or Pearson's chi-squared test. RESULTS: Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA-IR). CONCLUSIONS: Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors.

Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial.

AIM: To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms. MATERIALS AND METHODS: Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR). RESULTS: Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1). CONCLUSION: Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.

The Effects of Modifying Amount and Type of Dietary Carbohydrate on Esophageal Acid Exposure Time and Esophageal Reflux Symptoms: A Randomized Controlled Trial.

INTRODUCTION: This is the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic gastroesophageal reflux disease (GERD). METHODS: Ninety-eight veterans with symptomatic GERD were randomly assigned to high total/high simple, high total/low simple, low total/high simple, or low total/low simple carbohydrate diet for 9 weeks. The primary outcomes were esophageal acid exposure time (AET) and total number of reflux episodes derived from 24-hour ambulatory pH monitoring. Secondary outcomes were esophageal reflux symptoms rated using the Gastroesophageal Reflux Disease Questionnaire (GERDQ) and GERD Symptom Assessment Scale (GSAS). RESULTS: Half of the subjects were White and half African American (mean age, 60.0 ± 12.5 years; mean body mass index, 32.7 ± 5.4 kg/m 2 ). There was a significant main effect of diet treatment on AET ( P = 0.001) and on the total number of reflux episodes ( P = 0.003). The change in AET in the high total/low simple group (-4.3% ± 3.8%) differed significantly from the high total/high simple control group (+3.1% ± 3.7%), (P = 0.04). The reduction in simple sugar intake averaged 62 g less per day. Subjects' ratings of symptoms improved in all carbohydrate modification groups, including significant reductions in heartburn frequency, heartburn severity, acid taste in the mouth, lump/pain in the throat or chest, and sleep disturbance. DISCUSSION: A modification of dietary carbohydrate intake that targeted a substantial reduction in the intakes of simple sugars improved pH monitoring outcomes and symptoms of GERD that profoundly affect daily life. These findings provide a feasible and clinically applicable contribution to the limited objective data existing for efficacious dietary recommendations in the routine treatment and management of GERD.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist.

BACKGROUND/OBJECTIVES: Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure. SUBJECTS/METHODS: Forty-two patients aged 10-26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n = 23) or placebo (n = 19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference. RESULTS: As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (-1800 kJ (-430 kcal), 95% CI -3 184 to -418 kJ, p = 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (-372 kJ/day (-89 kcal/day), 95% CI -699 to -42 kJ/day, p = 0.04) or change in leptin (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p = 0.88 and 1.5 vs. 4.6 kg fat mass, p = 0.04, ExQW vs. placebo). CONCLUSIONS: Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

Ameliorative Role of Fluconazole Against Abdominal Aortic Constriction-Induced Cardiac Hypertrophy in Rats.

ABSTRACT: Cytochrome P450 1B1 (CYP1B1) is known to be involved in the pathogenesis of several cardiovascular diseases, including cardiac hypertrophy and heart failure, through the formation of cardiotoxic metabolites named as mid-chain hydroxyeicosatetraenoic acids (HETEs). Recently, we have demonstrated that fluconazole decreases the level of mid-chain HETEs in human liver microsomes, inhibits human recombinant CYP1B1 activity, and protects against angiotensin II-induced cellular hypertrophy in H9c2 cells. Therefore, the overall purpose of this study was to elucidate the potential cardioprotective effect of fluconazole against cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Male Sprague-Dawley rats were randomly assigned into 4 groups such as sham control rats, fluconazole-treated (20 mg/kg daily for 4 weeks, intraperitoneal) sham rats, AAC rats, and fluconazole-treated (20 mg/kg) AAC rats. Baseline and 5 weeks post-AAC echocardiography were performed. Gene and protein expressions were measured using real-time PCR and Western blot analysis, respectively. The level of mid-chain HETEs was determined using liquid chromatography-mass spectrometry. Echocardiography results showed that fluconazole significantly prevented AAC-induced left ventricular hypertrophy because it ameliorated the AAC-mediated increase in left ventricular mass and wall measurements. In addition, fluconazole significantly prevented the AAC-mediated increase of hypertrophic markers. The antihypertrophic effect of fluconazole was associated with a significant inhibition of CYP1B1, CYP2C23, and 12-LOX and a reduction in the formation rate of mid-chain HETEs. This study demonstrates that fluconazole protects against left ventricular hypertrophy, and it highlights the potential repurposing of fluconazole as a mid-chain HETEs forming enzymes' inhibitor for the protection against cardiac hypertrophy.

Obesity is Associated with Longer Survival Independent of Sarcopenia and Myosteatosis in Metastatic and/or Castrate-Resistant Prostate Cancer.

PURPOSE: Obesity (body mass index 30 kg/m2 or greater) is associated with better overall survival in metastatic prostate cancer. Conversely, low muscle mass (sarcopenia) and low muscle radiodensity (myosteatosis) are associated with worse overall survival in many cancers. This study seeks to evaluate the relationship of sarcopenia, myosteatosis and obesity with overall survival in men with metastatic or castrate-resistant prostate cancer. MATERIALS AND METHODS: Retrospective analysis of men with metastatic or castrate-resistant prostate cancer and computerized tomography of abdomen/pelvis presenting to the Vanderbilt Comprehensive Prostate Cancer Clinic from 2012 to 2017 was performed. Demographic, pathological and survival data were described, with sarcopenia and myosteatosis determined from abdominal skeletal muscle area and skeletal muscle radiodensity, respectively. Kaplan-Meier curves and log-rank tests estimated the effect of body composition on survival. Multivariable Cox proportional hazard models were performed adjusting for age, Charlson comorbidity index, race and clinical stage. ANOVA was used to compare obese and nonobese men with and without sarcopenia or myosteatosis. RESULTS: Of 182 men accrued, 37.4% were obese, 53.3% sarcopenic and 59.3% myosteatotic. Over a median followup of 33.9 months, body mass index was associated with reduced mortality (HR 0.93, p=0.02), as was visceral adiposity (HR 0.99, p=0.003). Men with high body mass index without sarcopenia/myosteatosis lived significantly longer than men with high body mass index with sarcopenia/myosteatosis or normal body mass index men (F[3,91]=4.03, p=0.01). CONCLUSIONS: Both high body mass index and visceral adiposity in metastatic or castrate-resistant prostate cancer are associated with reduced mortality, independent of sarcopenia and myosteatosis. Therefore, routine clinical workup should include calculation of body mass index and measurement of waist circumference. Morphometric analysis of computerized tomography imaging can identify patients at risk for poor prognosis.

New-onset vegetarian diet shows differences in fatty acid metabolites in European American and African American women.

BACKGROUND AND AIMS: The type of fat consumed in animal-based western diets, typically rich in the saturated fat palmitate, has been implicated in cardiometabolic disease risk. In contrast, the most abundant mono- and polyunsaturated fats, more typical in a vegetarian or plant-based diet, potentiate less deleterious effects. This study determined differences in plasma and urine metabolites when switching from omnivorous to vegetarian diet, including metabolites involved in fatty acid utilization. METHODS AND RESULTS: A prospective cohort of 38 European (EA) and African American (AA) omnivorous females were matched by age (25.7 ± 5.3y) and BMI (22.4 ± 1.9 kg/m2). Pre-intervention samples were collected while subjects consumed habitual animal-based diet. Changes in metabolites were assessed by ultra-high-performance liquid chromatography-tandem mass spectroscopy (Metabolon, Inc.) upon completing four days of novel vegetarian diet provided by the Vanderbilt Metabolic Kitchen. Changes in several diet-derived metabolites were observed, including increases in compounds derived from soy food metabolism along with decreases in metabolites of xanthine and histidine. Significant changes occurred in metabolites of saturated, monounsaturated and polyunsaturated fatty acids along with significant differences between EA and AA women in changes in plasma concentrations of acylcarnitines, which reflect the completeness of fatty acid oxidation (versus storage). CONCLUSION: These data suggest improvements in fatty acid metabolism (oxidation vs storage), a key factor in energy homeostasis, may be promoted rapidly by adoption of a vegetarian (plant-based) diet. Mechanistic differences in response to diet interventions must be understood to effectively provide protection against the widespread development of obesity and cardiometabolic disease in population subgroups, such as AA women.

Assessing Diet Quality in a Racially and Ethnically Diverse Cohort of Low-income Toddlers.

BACKGROUND: Low-income racially and ethnically diverse children are at higher risk for obesity compared with their counterparts; yet, few studies have assessed their diet quality. OBJECTIVE: The aim of the study was to evaluate the diet quality of a racially and ethnically diverse cohort of 2-year-olds using the Healthy Eating Index (HEI)-2010. METHODS: We used 24-hour dietary recall data from caregivers of toddlers (24-34 months) at 4 pediatric resident clinics that participated in the Greenlight Study to calculate compliance with the Dietary Guidelines for Americans (DGA) using total HEI score (range 0-100) and 12 component scores. RESULTS: Participants (n = 231) were mostly Hispanic (57%) or non-Hispanic black (27%) and from low-income families. Mean HEI-2010 score was 62.8 (standard deviation [SD] 10.5). Though not significant, Hispanics had the highest HEI score. Toddlers of caregivers without obesity, older than 35 years and born outside the United States had higher HEI scores. Most had high HEI component scores for dairy, fruit, and protein foods, but few achieved maximum scores, particularly for whole grains (13%), vegetables (10%), and fatty acid ratio (7%). CONCLUSIONS: Despite scores reflective of DGA recommendations for fruit, dairy and protein foods, toddlers in this diverse sample had low quality diets as measured by the HEI, driven largely by low component scores for whole grains, vegetables, and ratio of unsaturated to saturated fatty acids.

Perioperative Oral Nutrition Supplementation Reduces Prevalence of Sarcopenia following Radical Cystectomy: Results of a Prospective Randomized Controlled Trial.

PURPOSE: We designed a prospective randomized, controlled pilot trial to investigate the effects of an enriched oral nutrition supplement on body composition and clinical outcomes following radical cystectomy. MATERIALS AND METHODS: A total of 61 patients were randomized to an oral nutrition supplement or a multivitamin multimineral supplement twice daily during an 8-week perioperative period. Body composition was determined by analyzing abdominal computerized tomography images at the L3 vertebra. Sarcopenia was defined as a skeletal muscle index of less than 55 cm/m in males and less than 39 cm/m in females. The primary outcome was the difference in 30-day hospital free days. Secondary outcomes included hospital length of stay, complications, readmissions and mortality. RESULTS: The oral nutrition supplement group lost less weight (-5 vs -6.5 kg, p = 0.04) compared to the multivitamin multimineral supplement group. The proportion of patients with sarcopenia did not change in the oral nutrition supplement group but increased 20% in the multivitamin multimineral supplement group (p = 0.01). Mean length of stay and 30-day hospital free days were similar in the groups. The oral nutrition supplement group had a lower rate of overall and major (Clavien grade 3 or greater) complications (48% vs 67% and 19% vs 25%, respectively) and a lower readmission rate (7% vs 17%) but the differences did not reach statistical significance. CONCLUSIONS: Patients who undergo radical cystectomy after consuming an oral nutrition supplement perioperatively have a reduced prevalence of sarcopenia and may also experience fewer and less severe complications and readmissions. A larger blinded, randomized, controlled trial is necessary to determine whether oral nutrition supplement interventions can improve outcomes following radical cystectomy.

Poorly controlled glycemia and worse beta cell function associate with higher resting and total energy expenditure in adults with obesity and type 2 diabetes: A doubly labeled water study.

BACKGROUND: Some studies comparing persons with and without type 2 diabetes (T2DM) show no difference in resting energy expenditure (REE). However, the degree of glycemic control may be a crucial factor in determining energy requirements. Few studies have employed the doubly labeled water (DLW) method in persons with T2DM to objectively measure daily energy expenditure. AIMS: To determine relationships between glycemia, body composition, and energy expenditure in adults with obesity and T2DM. We hypothesized that worse hyperglycemia, insulin resistance, and beta cell function would associate with higher resting and total energy expenditure (TEE). METHODS: Two cohorts age 31-50 years were included: 78 with obesity and T2DM, 19 with normal weight and no chronic disease. Baseline data from clinical biomarkers, intravenous glucose tolerance tests, DXA and MRI for body composition, and dietary intakes were used in multivariable regression models to predict REE and TEE. Additionally, comparisons were made by categorizing participants as having controlled or uncontrolled glycemia based on glucose levels ≥175 mg/dL. RESULTS: REE was higher in participants with T2DM by 534.08 ± 74.35 kcal/d (p < 0.001). Higher fasting glucose and HbA1C levels associated with higher TEE. Abdominal SAT and VAT were also predictors in regression models accounting for 76 % of the variance in REE and 89 % of TEE. Participants with uncontrolled glycemia had 22 % higher adipose/lean ratio, two-fold higher VAT/SAT ratio, 21 % higher HOMA-IR score, and worse beta cell function (mean difference in HOMA2-%ß of 74.09 ± 14.01, p < 0.001) than those with controlled glycemia. Both REE and TEE were significantly higher in uncontrolled glycemia, difference in REE of 154.17 ± 96.28 kcals/day (p = 0.04) and difference in TEE of 480.64 ± 215.45 kcals/day (p = 0.03). CONCLUSIONS: Poor beta cell function and uncontrolled glycemia associate with higher REE and TEE in persons with obesity and T2DM. This study is registered with clinicaltrials.gov identifier: NCT01239550.

Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes.

Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. ARTICLE HIGHLIGHTS: Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.

Cardiometabolic Characteristics of Obesity Phenotypes in Persons With HIV.

Background: In the general population, it is established that adipose tissue depots pose various risks for cardiometabolic diseases. The interaction among obesity, HIV, and antiretroviral treatment promotes even greater risk for persons with HIV (PWH). As obesity is a heterogeneous condition, determining the specific obesity phenotypes present and their characteristics is critical to personalize care in PWH. Methods: Visceral, sarcopenic, myosteatotic, hepatosteatotic, and metabolically healthy obesity phenotypes were determined by pre-established cut points after segmentation of computed tomography scans at the L3 vertebra. Multivariable linear regression modeling included anthropometrics, clinical biomarkers, and inflammatory factors while controlling for age, sex, race, and body mass index (BMI). Results: Of 187 PWH, 86% were male, and the mean ± SD age and BMI were 51.2 ± 12.3 years and 32.6 ± 6.3 kg/m2. Overall, 59% had visceral obesity, 11% sarcopenic obesity, 25% myosteatotic obesity, 9% hepatosteatotic obesity, and 32% metabolically healthy obesity. The strongest predictor of visceral obesity was an elevated triglyceride:high-density lipoprotein (HDL) ratio. Increased subcutaneous fat, waist circumference, and HDL cholesterol were predictors of sarcopenic obesity. Diabetes status and elevated interleukin 6, waist circumference, and HDL cholesterol predicted myosteatotic obesity. An increased CD4+ count and a decreased visceral:subcutaneous adipose tissue ratio predicted hepatosteatotic obesity, though accounting for only 28% of its variability. Participants with metabolically healthy obesity were on average 10 years younger, had higher HDL, lower triglyceride:HDL ratio, and reduced CD4+ counts. Conclusions: These findings show that discrete obesity phenotypes are highly prevalent in PWH and convey specific risk factors that measuring BMI alone does not capture. These clinically relevant findings can be used in risk stratification and optimization of personalized treatment regimens. This study is registered at ClinicalTrials.gov (NCT04451980).

Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation.

BACKGROUND: Cardiac glucose oxidation is decreased in heart failure with reduced ejection fraction (HFrEF), contributing to a decrease in myocardial ATP production. In contrast, circulating ketones and cardiac ketone oxidation are increased in HFrEF. Since ketones compete with glucose as a fuel source, we aimed to determine whether increasing ketone concentration both chronically with the SGLT2 inhibitor, dapagliflozin, or acutely in the perfusate has detrimental effects on cardiac glucose oxidation in HFrEF, and what effect this has on cardiac ATP production. METHODS: 8-week-old male C57BL6/N mice underwent sham or transverse aortic constriction (TAC) surgery to induce HFrEF over 3 weeks, after which TAC mice were randomized to treatment with either vehicle or the SGLT2 inhibitor, dapagliflozin (DAPA), for 4 weeks (raises blood ketones). Cardiac function was assessed by echocardiography. Cardiac energy metabolism was measured in isolated working hearts perfused with 5 mM glucose, 0.8 mM palmitate, and either 0.2 mM or 0.6 mM ß-hydroxybutyrate (ßOHB). RESULTS: TAC hearts had significantly decreased %EF compared to sham hearts, with no effect of DAPA. Glucose oxidation was significantly decreased in TAC hearts compared to sham hearts and did not decrease further in TAC hearts treated with high ßOHB or in TAC DAPA hearts, despite ßOHB oxidation rates increasing in both TAC vehicle and TAC DAPA hearts at high ßOHB concentrations. Rather, increasing ßOHB supply to the heart selectively decreased fatty acid oxidation rates. DAPA significantly increased ATP production at both ßOHB concentrations by increasing the contribution of glucose oxidation to ATP production. CONCLUSION: Therefore, increasing ketone concentration increases energy supply and ATP production in HFrEF without further impairing glucose oxidation.

Single-cell Analysis of Subcutaneous Fat Reveals Pro-fibrotic Cells that Correlate with Visceral Adiposity in HIV.

CONTEXT: Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH. OBJECTIVE: We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART. METHODS: We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using HOMA2-IR. RESULTS: VAT volume was associated with HOMA2-IR (p < 0.001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC + fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (ρ=0.34-0.49, p < 0.05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)- and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism-associated genes. CONCLUSIONS: In PWH, greater VAT volume is associated with higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms.

Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. METHODS AND RESULTS: Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. CONCLUSION: In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.