Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance

Abstract

ObjectiveBreakthroughs in HIV treatment, especially combination antiretroviral therapy (ART), have massively reduced AIDS-associated mortality. However, ART administration amplifies the risk of non-AIDS defining illnesses including obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. Initial reports suggest that ART-associated risk of metabolic syndrome correlates with socioeconomic status, a multifaceted finding that encompasses income, race, education, and diet. Therefore, determination of causal relationships is extremely challenging due to the complex interplay between viral infection, ART, and the many environmental factors.MethodsIn the current study, we employed a mouse model to specifically examine interactions between ART and diet that impacts energy balance and glucose metabolism. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages.ResultsART-treated mice on a HFD displayed increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation.ConclusionThe current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways and impairs glucose metabolism, energy balance, and metabolic dysfunction.

Resident macrophages reprogram toward a developmental state after acute kidney injury

“…Sequenced samples were then inspected for quality using Multiqc (70) to ensure PHRED >30. Reads were aligned and annotated to the Gencode mus musculus genome (GRCm38) using STAR (71), transcript abundances (raw counts) were calculated using HTSeq-Count version 0.9.1, and differential gene expression performed using DESeq2 (72) (1.18.1) within the R (3.4.2) statistical computing environment, as described previously (73), with project-specific details outlined in the Supplemental Methods. To address sample-size constraints (n = 3), aligned count dispersion estimates were determined via maximum likelihood to assume that genes of similar average expression strength possess similar dispersion, as previously described (72).…”

The Bi-directional Relationship Between Childhood Malnutrition and HIV/AIDS

“…Notwithstanding, several other studies have reported a transition to overweight/obesity following initiation of ART (29-31, 33, 39, 40). In mouse models, ART has also been shown to increase diet-induced obesity, impair glucose metabolism and genetically alter fat tissue (41). A study in Zimbabwe even reveals a higher prevalence of HIV-positive overweight/obese children than underweight ones (32).…”

“…A study in Zimbabwe even reveals a higher prevalence of HIV-positive overweight/obese children than underweight ones (32). The effect of ART on weight gain is more pronounced among the female and black populations (41)(42)(43). Lipodystrophy, a known complication of ART drugs has also been found to be significant in children (44,45).…”

Examining Relationships between Metabolism and Persistent Inflammation in HIV Patients on Antiretroviral Therapy

“…While the etiology of this morbidity is likely multifactorial, the synergistic effects of obesity on persistent systemic inflammation observed in HIV patients on ART may play a role in amplifying this risk [ 98 , 99 ]. Interestingly, a recent study in mice found that ART treatment on a high-fat diet was associated with increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance compared to those on low-fat diet, suggesting that high-fat diets may further amplify the metabolic effects of ART [ 100 ]. This cumulative metabolic dysfunction was associated with augmented proinflammatory signaling within adipose tissue consistent with macrophage infiltration [ 100 ].…”

“…Interestingly, a recent study in mice found that ART treatment on a high-fat diet was associated with increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance compared to those on low-fat diet, suggesting that high-fat diets may further amplify the metabolic effects of ART [ 100 ]. This cumulative metabolic dysfunction was associated with augmented proinflammatory signaling within adipose tissue consistent with macrophage infiltration [ 100 ]. These findings need to be validated in HIV patients on ART.…”