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.

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.

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).

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.

Consumption of Tree Nuts as Snacks Reduces Metabolic Syndrome Risk in Young Adults: A Randomized Trial.

Metabolic syndrome (MetSx) and its chronic disease consequences are major public health concerns worldwide. Between-meal snacking may be a modifiable risk factor. We hypothesized that consuming tree nuts as snacks, versus typical carbohydrate snacks, would reduce risk for MetSx in young adults. A prospective, randomized, 16-week parallel-group diet intervention trial was conducted in 84 adults aged 22-36 with BMI 24.5 to 34.9 kg/m2 and ≥1 MetSx clinical risk factor. Tree nuts snacks (TNsnack) were matched to carbohydrate snacks (CHOsnack) for energy (kcal), protein, fiber, and sodium content as part of a 7-day eucaloric menu. Difference in change between groups was tested by analysis of covariance using general linear models. Multivariable linear regression modeling assessed main effects of TNsnack treatment and interactions between TNsnack and sex on MetSx score. Age, BMI, and year of study enrollment were included variables. There was a main effect of TNsnack on reducing waist circumference in females (mean difference: -2.20 ± 0.73 cm, p = 0.004) and a trend toward reduced visceral fat (-5.27 ± 13.05 cm2, p = 0.06). TNsnack decreased blood insulin levels in males (-1.14 ± 1.41 mIU/L, p = 0.05) and multivariable modeling showed a main effect of TNsnack on insulin. Main effects of TNsnack on triglycerides and TG/HDL ratio were observed (p = 0.04 for both) with TG/HDL ratio reduced ~11%. A main effect of TNsnack (p = 0.04) and an interaction effect between TNsnack and sex (p < 0.001) on total MetSx score yielded 67% reduced MetSx score in TNsnack females and 42% reduced MetSx score in TNsnack males. To our knowledge, this is the first randomized parallel-arm study to investigate cardiometabolic responses to TNsnacks versus typical CHOsnacks among young adults at risk of MetSx. Our study suggests daily tree nut consumption reduces MetSx risk by improving waist circumference, lipid biomarkers, and/or insulin sensitivity-without requiring caloric restriction.