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.

Immune Cell Activation in Obesity and Cardiovascular Disease.

PURPOSE OF REVIEW: In this review, we focus on immune cell activation in obesity and cardiovascular disease, highlighting specific immune cell microenvironments present in individuals with atherosclerosis, non-ischemic heart disease, hypertension, and infectious diseases. RECENT FINDINGS: Obesity and cardiovascular disease are intimately linked and often characterized by inflammation and a cluster of metabolic complications. Compelling evidence from single-cell analysis suggests that obese adipose tissue is inflammatory and infiltrated by almost all immune cell populations. How this inflammatory tissue state contributes to more systemic conditions such as cardiovascular and infectious disease is less well understood. However, current research suggests that changes in the adipose tissue immune environment impact an individual's ability to combat illnesses such as influenza and SARS-CoV2. Obesity is becoming increasingly prevalent globally and is often associated with type 2 diabetes and heart disease. An increased inflammatory state is a major contributor to this association. Widespread chronic inflammation in these disease states is accompanied by an increase in both innate and adaptive immune cell activation. Acutely, these immune cell changes are beneficial as they sustain homeostasis as inflammation increases. However, persistent inflammation subsequently damages tissues and organs throughout the body. Future studies aimed at understanding the unique immune cell populations in each tissue compartment impacted by obesity may hold potential for therapeutic applications.

Anticytomegalovirus CD4+ T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV.

[Figure: see text].

The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells.

Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.

Association of a glucagon-like peptide-1 receptor gene variant with glucose response to a mixed meal.

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous glucagon-like peptide-1 (GLP-1). We hypothesized that genetic variation in the gene encoding the GLP-1 receptor (GLP1R) could affect the metabolic response to DPP-4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G-to-A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7-day treatment with placebo and the DPP-4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP-1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP-1 signalling merits study in large populations.

CD8α(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites.

CD8α(+) dendritic cells (DCs) are important in vivo for cross-presentation of antigens derived from intracellular pathogens and tumors. Additionally, secretion of interleukin-12 (IL-12) by CD8α(+) DCs suggests a role for these cells in response to Toxoplasma gondii antigens, although it remains unclear whether these cells are required for protection against T. gondii infection. Toward this goal, we examined T. gondii infection of Batf3(-/-) mice, which selectively lack only lymphoid-resident CD8α(+) DCs and related peripheral CD103(+) DCs. Batf3(-/-) mice were extremely susceptible to T. gondii infection, with decreased production of IL-12 and interferon-γ. IL-12 administration restored resistance in Batf3(-/-) mice, and mice in which IL-12 production was ablated only from CD8α(+) DCs failed to control infection. These results reveal that the function of CD8α(+) DCs extends beyond a role in cross-presentation and includes a critical role for activation of innate immunity through IL-12 production during T. gondii infection.

Compensatory dendritic cell development mediated by BATF-IRF interactions.

The AP1 transcription factor Batf3 is required for homeostatic development of CD8α(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8α(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.

Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells.

T cells are essential for immune defenses against pathogens, such that viability of naïve T cells before antigen encounter is critical to preserve a polyclonal repertoire and prevent immunodeficiencies. The viability of naïve T cells before antigen recognition is ensured by IL-7, which drives expression of the prosurvival factor Bcl-2. Quiescent naïve T cells have low basal activity of the transcription factor NF-κB, which was assumed to have no functional consequences. In contrast to this postulate, our data show that basal nuclear NF-κB activity plays an important role in the transcription of IL-7 receptor α-subunit (CD127), enabling responsiveness of naïve T cells to the prosurvival effects of IL-7 and allowing T-cell persistence in vivo. Moreover, we show that this property of basal NF-κB activity is shared by mouse and human naïve T cells. Thus, NF-κB drives a distinct transcriptional program in T cells before antigen encounter by controlling susceptibility to IL-7. Our results reveal an evolutionarily conserved role of NF-κB in T cells before antigenic stimulation and identify a novel molecular pathway that controls T-cell homeostasis.

The polymorphic pseudokinase ROP5 controls virulence in Toxoplasma gondii by regulating the active kinase ROP18.

Secretory polymorphic serine/threonine kinases control pathogenesis of Toxoplasma gondii in the mouse. Genetic studies show that the pseudokinase ROP5 is essential for acute virulence, but do not reveal its mechanism of action. Here we demonstrate that ROP5 controls virulence by blocking IFN-γ mediated clearance in activated macrophages. ROP5 was required for the catalytic activity of the active S/T kinase ROP18, which phosphorylates host immunity related GTPases (IRGs) and protects the parasite from clearance. ROP5 directly regulated activity of ROP18 in vitro, and both proteins were necessary to avoid IRG recruitment and clearance in macrophages. Clearance of both the Δrop5 and Δrop18 mutants was reversed in macrophages lacking Irgm3, which is required for IRG function, and the virulence defect was fully restored in Irgm3(-/-) mice. Our findings establish that the pseudokinase ROP5 controls the activity of ROP18, thereby blocking IRG mediated clearance in macrophages. Additionally, ROP5 has other functions that are also Irgm3 and IFN-γ dependent, indicting it plays a general role in governing virulence factors that block immunity.

Systemic and organ-specific anti-inflammatory effects of sodium-glucose cotransporter-2 inhibitors.

Inflammation plays an essential role and is a common feature in the pathogenesis of many chronic diseases. The exact mechanisms through which sodium-glucose cotransporter-2 (SGLT2) inhibitors achieve their much-acclaimed clinical benefits largely remain unknown. In this review, we detail the systemic and tissue- or organ-specific anti-inflammatory effects of SGLT2 inhibitors using evidence from animal and human studies. We discuss the potential pathways through which SGLT2 inhibitors exert their anti-inflammatory effects, including oxidative stress, mitochondrial, and inflammasome pathways. Finally, we highlight the need for further investigation of the extent of the contribution of the anti-inflammatory effects of SGLT2 inhibition to improvements in cardiometabolic and renal outcomes in clinical studies.

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.

Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV.

Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.

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.

The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.

OBJECTIVE: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. METHODS: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. RESULTS: We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. CONCLUSIONS: SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non-immune populations in SAT and is shared with VAT, nuancing the current VAT-centric concept of IR in humans.

Metaflammation in obesity and its therapeutic targeting.

Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation.

Single cell RNA-sequencing suggests a novel lipid associated mast cell population following weight cycling.

Our recent study showed weight cycled mice have increased adipose mast cells compared to obese mice by single cell RNA-sequencing. Here, we aimed to confirm and elucidate these changes. Further analysis of our dataset showed that our initial mast cell cluster could subcluster into two unique populations: one with very high expression of classical mast cell markers and another with elevated lipid handling and antigen presentation genes. This new mast cell cluster accounted for most of the mast cells in the weight cycled group although it was not possible to detect the different populations by new studies with flow cytometry or Toluidine blue staining in mice, possibly due to a downregulation in classical mast cell genes. Interestingly, a pilot study in humans did suggest the existence of two mast cell populations in subcutaneous adipose tissue from obese women that appear similar to the murine populations detected by sequencing; one of which was significantly correlated with weight variance. Together, these data suggest that weight cycling may induce a unique population of mast cells similar to lipid associated macrophages. Future studies will focus on isolation of these cells to better determine their lineage, differentiation, and functional roles.

Changes in subcutaneous white adipose tissue cellular composition and molecular programs underlie glucose intolerance in persons with HIV.

Introduction: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. Methods: We generated a comprehensive single-cell multi-omic SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH across a spectrum of metabolic health. Results: Glucose intolerance was associated with increased lipid-associated macrophages, CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue-resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Intercellular communication analysis demonstrated enhanced pro-inflammatory and pro-fibrotic signaling between immune cells and stromal cells in PWH with glucose intolerance compared with non-diabetic PWH. Lastly, while cell type-specific gene expression among PWH with diabetes was globally similar to HIV-negative individuals with diabetes, we observed substantially divergent intercellular communication pathways. Discussion: These findings suggest a central role of tissue-resident immune cells in regulating SAT inflammation among PWH with metabolic disease, and underscore unique mechanisms that may converge to promote metabolic disease.

CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV.

Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1+, GPR56+, and CD57+/- T cells (termed CGC+) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid ß-oxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+. Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals.