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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 proinflammatory 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Serum periostin is lower in asthmatics with T2DM using GLP-1RAs compared to alternative diabetes therapies. Prior studies identifying candidate biomarkers of GLP-1RA use critically lacked inclusion of patients with asthma.[[4]] Increasing data support periostin as a potential biomarker of GLP-1RA use. In conclusion, GLP-1RA use may attenuate the increased risk for poor asthma outcomes in patients with metabolic dysregulation and obesity by impacting pathways relevant to airway inflammation in humans. Consistent with prior asthma literature, patients with comorbid asthma (Biobank cohort) had higher mean levels of periostin than the non-asthma patients (RCT cohort). [Extracted from the article]

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 longterm 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 boxidation. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Summary: 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. [ABSTRACT FROM AUTHOR]

Persons with human immunodeficiency virus (PWH) have subcutaneous adipose tissue (SAT) dysfunction related to antiretroviral therapy and direct viral effects, which may contribute to a higher risk of nonalcoholic fatty liver disease compared with human immunodeficiency virus–negative individuals. We assessed relationships between SAT expression of major adipocyte regulatory and lipid storage genes with hepatic and other ectopic lipid deposits in PWH. We enrolled 97 PWH on long‐term antiretroviral therapy with suppressed plasma viremia and performed computed tomography measurements of liver attenuation, a measure of hepatic steatosis, skeletal muscle (SM) attenuation, and the volume of abdominal subcutaneous, visceral, and pericardial adipose tissue. Whole SAT gene expression was measured using the Nanostring platform, and relationships with computed tomography imaging and fasting lipids were assessed using multivariable linear regression and network mapping. The cohort had a mean age of 47 years, body mass index of 33.4 kg/m2, and CD4 count of 492 cells/mm3. Lower liver attenuation, a marker of greater steatosis, was associated with differences in SAT gene expression, including lower lipoprotein lipase and acyl‐CoA dehydrogenase, and higher phospholipid transfer protein. Lower liver attenuation clustered with lower visceral adipose tissue (VAT) attenuation and greater VAT volume, pericardial fat volume and triglycerides, but no relationship was observed between liver attenuation and SAT volume, SM attenuation, or low‐density lipoprotein. Conclusion: Liver attenuation was associated with altered SAT expression of genes regulating lipid metabolism and storage, suggesting that SAT dysfunction may contribute to nonalcoholic fatty liver disease in PWH. SAT gene‐expression relationships were similar for VAT volume and attenuation, but not SM, indicating that ectopic lipid deposition may involve multiple pathways. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 naive T cells before antigen recognition is ensured by IL-7, which drives expression of the prosurvival factor Bcl-2. Quiescent naive 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 a-subunit (CD127), enabling responsiveness of naive 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The AP1 transcription factor Batf3 is required for homeostatic development of CD8?+ classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8?+ dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-?. 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. [ABSTRACT FROM AUTHOR]

Commitment of hematopoietic progenitors to the T cell lineage requires the integration of multiple signaling pathways. Evidence has suggested involvement of hedgehog (Hh) signaling in T cell differentiation through its signal transducer smoothened (Smo). However, the precise function of the Hh pathway remains controversial, mainly because T cell–specific in vivo genetic models have not been used. Using pre–T cell–specific, mature T cell–specific and poly(I)·poly(C)-inducible deletions of Smo and antagonists of Smo signaling, we report here that Hh is an essential positive regulator of T cell progenitor differentiation. Furthermore, we localize Hh function to a stage preceding pre–T cell receptor signaling, connect Smo signaling to the activity of the Gli1 and Gli2 transcription factors and demonstrate that Hh affects regulators of thymocyte survival and proliferation. [ABSTRACT FROM AUTHOR]