Adipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV.

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.

Heightened levels of plasma growth differentiation factor 15 in men living with HIV.

Plasma biomarkers that reflect energy balance disorders in people living with HIV (PLWH) remain limited. Growth differentiation factor 15 (GDF15) abundance in plasma of mice and humans induces negative energy balance but also becomes highly elevated in obesity and other metabolic diseases. We sought to compare plasma GDF15 levels in PLWH and HIV-negative persons and mouse models expressing the HIV accessory protein Vpr (that recapitulate HIV-associated metabolic disorders) and determine their relationship to metabolic parameters. We measured liver Gdf15 mRNA levels and plasma GDF15 levels in male Vpr mice and littermate controls. In parallel, we analyzed plasma GDF15 levels in 18 male PLWH on stable, long-term antiretroviral therapy and 13 HIV-negative men (6 healthy controls and 7 with metabolic syndrome). Plasma GDF15 levels were correlated with anthropometric and immune cell parameters in humans. Gene expression analysis of Vpr mouse liver demonstrated elevated Gdf15 mRNA. Plasma GDF15 levels were also higher in Vpr mouse models. Levels of plasma GDF15 in PLWH were greater than in both HIV-negative groups and correlated positively with the CD4/CD8 T cell ratio in PLWH. Plasma GDF15 levels correlated positively with age in the HIV-negative subjects but not in PLWH. Since GDF15 levels predict fatty liver disease and energy balance disorders, further studies are warranted to determine the effect of GDF15 in mediating the metabolic disturbances that occur in Vpr mice and PLWH.

DPP4 (Dipeptidyl Peptidase-4) Inhibition Increases Catecholamines Without Increasing Blood Pressure During Sustained ACE (Angiotensin-Converting Enzyme) Inhibitor Treatment.

BACKGROUND: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. METHODS: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. RESULTS: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. CONCLUSIONS: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.