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Antiretroviral therapy has improved life expectancy among people living with HIV (PLWH). Despite increased longevity, PLWH are at increased risk of age-related comorbidities, including frailty. We examined the relationship between body composition and frailty among PLWH, and moderation of this relationship by substance use, physical activity (PA), and physical function.Participants (n = 341; 71% male, 48 ± 10 years, body mass index (BMI) = 27.3 ± 7.0 kg/mMultivariable linear regression adjusted for age, sex, and race showed that higher fat-free mass index (FFMI), body fat (%), waist-to-hip ratio, and body mass index (BMI) ≥ 25.0 kg/mOur findings indicate that body composition has significant modulatory effects on frailty risk in PLWH, where obesity increases the risk of frailty and greater muscle mass may be protective, even in individuals who use alcohol. These results highlight the importance of considering body composition, physical activity, and physical function in assessing frailty risk in PLWH, particularly among individuals who use alcohol. Moreover, they support the implementation of physical activity interventions to ameliorate the risk of frailty in aging PLWH.

Background: Alcohol-related liver injury includes steatosis, fibrosis, and inflammation, which can culminate in alcoholic hepatitis and cirrhosis. The pre-clinical alterations in gene expression underlying these pathophysiological changes are ill-defined. Chronic binge alcohol (CBA) consumption produces marked alterations in metabolic processes and our studies show this is accentuated in chronic infection such as in HIV. This study tested the hypothesis that CBA disrupts expression of hepatic genes involved in glycolytic, gluconeogenic, and lipid turnover pathways in rhesus macaques infected with simian immunodeficiency virus (SIV). Methods: Female rhesus macaques were administered CBA (13-14g ethanol/kg/week, n=7) or vehicle (VEH, n=8) starting 3 months prior to SIV infection. All animals were treated with anti-retroviral therapy starting at 2.5 months post-SIV infection and sacrificed at 14.5 months and liver samples obtained for histological analysis, determination of gene expression by qPCR, triglyceride content by colorimetric assay, and pyruvate kinase activity by a colorimetric enzymatic assay. Results: Expression of lipid handling genes including perilipin 1, peroxisome proliferator-activated receptor γ (PPARγ), carbohydrate responsive binding protein (CHREBP), and acetyl-CoA carboxylase B were higher in CBA-treated compared to VEH-treated macaques. Expression of glycolytic (phosphofructokinase) and gluconeogenic (pyruvate carboxylase) enzymes including aldolase A was increased in the CBA group compared to VEH. No changes were observed in expression of the β-oxidation regulatory protein PPARα. Triglyceride content and pyruvate kinase activity were not significantly different between the groups. Conclusions: These results show significant CBA-mediated alteration of mRNA expression of lipid handling genes that could reflect increased lipid turnover despite lack of alterations in hepatic triglyceride content. Future studies will confirm the findings with protein expression of the differentially regulated genes and levels of non-esterified fatty acid in the liver. Supported by T32AA007577 & P60AA009803. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

At-risk alcohol use in people living with HIV (PLWH) and chronic binge alcohol (CBA) administration in simian immunodeficiency virus (SIV)-infected macaques are associated with dysfunctional skeletal muscle mass. Our studies have shown that decreased myomiR-206 expression in skeletal muscle and myoblasts isolated from CBA/SIV macaques contributes to decreased myoblast differentiation. miRs transported in extracellular vesicles (EVs) mediate numerous cellular responses through intercellular communication. This study tested the hypothesis that delivery of miR-206 in EVs would ameliorate CBA-mediated decreased myoblast differentiation. Eight female rhesus macaques received either (CBA, 2.5g/kg/day) or water (VEH) for 14.5 months. Three months following the initiation of CBA/VEH, animals were infected with SIVmac251 and initiated on antiretroviral therapy 2.5 months later. Myoblasts were isolated from the vastus lateralis muscle at study endpoint (blood alcohol concentration= 0 mM) from each animal and used for ex vivo experiments including measuring differentiation, transfecting with a miR-206 mimic, and isolating EVs from myotube culture supernatant via ultracentrifugation. Myoblast differentiation measured by fusion index was lower in CBA myotubes compared to VEH (p Supported by: NIH/NIAAA P60AA009803, F30AA029358, K01AA024494. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Adipose tissue maladaptation is central to metabolic dysregulation seen with calorie-dense, or Western, diets and at-risk alcohol use. We hypothesized that combining these conditions would produce greater adipose tissue maladaptation. The objective of this study was to determine the combined effects of a calorie-dense diet and chronic binge alcohol (CBA) on omental adipose tissue expression of genes that contribute to mitochondrial and metabolic alterations. Omental adipose samples used in the present study were obtained from a subset of animals included in an ongoing parent longitudinal study. Male rhesus macaques were fed ad libitum a high fat, high sucrose diet (HFSD; 41.7% fat and 27% sucrose) for 15.5 months. Starting at 3 months, animals received water (VEH) or CBA (13-14 g/kg/week) through a gastric catheter for the remainder of the study. Omental adipose biopsy samples were collected at the 3- and 7-month timepoints of HFSD feeding and 24 hours following the last alcohol dose. Samples included in this study were as follows: 3-months HFSD (n=5, HFSD), 7-months HFSD + VEH (n=5, VEH/HFSD), 7-months HFSD + CBA (n=5, CBA/HFSD), and bio-banked control-diet fed macaques (n=6, CTRL). Expression of genes associated with glucose and lipid metabolism, insulin sensitivity and mitochondrial health were determined using qRT-PCR. Gene expression of peroxisome proliferator-activated receptor γ, carbohydrate response element binding protein and adiponectin were decreased in HFSD compared to CTRL macaques. HFSD increased gene expression of interleukin 6 compared to CTRL macaques. Gene expression of peroxisome proliferator-activated receptor γ, hormone sensitive lipase and peroxisome proliferator-activated receptor γ coactivator 1-beta were decreased in macaques fed CBA/HFSD compared to VEH/HFSD macaques. Preliminary results indicate HFSD and CBA alter gene expression reflecting omental adipose metabolic and insulin dyshomeostasis and possibly decreased mitochondrial biogenesis and favors an inflammatory milieu. We predict these alterations in omental adipose tissue gene expression may translate into more severe metabolic dysregulation in HFSD fed CBA-treated animals. Supported by NIH/NIAAA P60 AA009803 and 1F31AA028459-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Introduction: Chronic alcohol administration produces significant metabolic dysfunction as determined in pre-clinical and clinical studies. Our studies using a rodent model of chronic alcohol feeding showed that alcohol induces mesenteric lymphatic leakage and perilymphatic adipose tissue (PLAT) immunometabolic dysregulation. Specifically, chronic alcohol induced localized PLAT inflammation and decreased glucose uptake. Whether chronic alcohol-induced lymphatic leakage is also associated with altered systemic glucose/insulin dynamics remained to be determined. We hypothesized that chronic alcohol feeding impairs the endocrine response to a glucose tolerance test. Methods: Male Fischer 344 rats were randomized to a Lieber-DeCarli liquid diet containing 36% of calories from alcohol or pair-fed an isocaloric diet for 10 weeks. Animals consumed approximately 75 mL of diet per day. Body weights were not significantly different between groups; the average weights were 275.7 grams for control animals and 275.9 grams for alcohol-fed animals. Weights in both groups remained stable for the duration of the study. At 10 weeks, animals were fasted for 16 hours prior to intraperitoneal (IP) injections of 20% glucose solution (2g/kg). Blood samples were collected from the rat tail prior to and at 15-minute intervals following initial glucose injection for 2 hours. Blood glucose was tested at each interval using the AlphaTRAK glucometer. 2-way ANOVA and paired T-test were used to assess significant differences between groups. Results and Conclusion: Prior to IP glucose injection, blood glucose levels averaged 77 mg/dL for control animals and 71.5 mg/dL for alcohol-fed animals. Glucose levels in alcohol-fed animals averaged 38% higher at 15 minutes and 37% higher 30 minutes after IP glucose bolus than that of control animals. Total area under the curve (AUC) calculated from the glucose concentrations measured following IP glucose injection was significantly higher in alcohol-fed animals compared to control animals; average AUC for alcohol-fed animals was 26.8% higher than AUC for control animals. These results suggest that chronic alcohol-induced mesenteric lymphatic leakage and localized PLAT inflammation and altered glucose metabolism are also associated with disturbances in systemic glucose dysregulation. Future studies will examine the potential link between alcohol-induced PLAT immunometabolic dysregulation and alterations in systemic glucose metabolism. Supported by T32 (PM), K01 (FS). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Human immunodeficiency virus (HIV) infection is detrimental to central nervous system (CNS) function and may result in HIV-associated neurocognitive disorder (HAND) over time. HIV-associated cognitive deficits are further exacerbated by chronic alcohol use. With the rising prevalence of alcohol use disorder (AUD) in females and people living with HIV (PLWH), understanding the neurobiological impact of chronic alcohol exposure in these populations is increasingly important. As the hippocampus plays a prominent role in cognition, examining neuroadaptations in this brain region in the context of comorbid HIV infection and alcohol exposure is critical for understanding the mechanisms of neurocognitive impairment. We hypothesized that simian immunodeficiency virus (SIV)-infected female rhesus macaques with a history of chronic binge alcohol (CBA) administration (n=7-8 per group) would exhibit increased phosphorylation of mitogen-activated protein kinase (MAPK) family members, indicative of increased hippocampal activity and potential hyperexcitability. We also measured cognitive performance in macaques via the novel object recognition (NOR) task and further hypothesized a manifestation of cognitive deficits in the CBA-treated group. Finally, we incorporated additional groups of ovariectomized (OVX) females in the design as we hypothesized that the loss of ovarian hormones would reduce cognitive performance. Data were analyzed via two-way ANOVA with CBA treatment and OVX as factors. Western blot analyses demonstrated that CBA significantly increased phosphorylation of MAPK-family members extracellular signal-regulated kinase (ERK; F=8.278, p=0.0093) and p38 mitogen-activated protein kinase (p38 MAPK; F=4.414, p=0.0485). Furthermore, CBA significantly increased both phosphorylated and total levels of Jun N-terminal kinase (JNK; F=5.989, p=0.0233; F=7.158, p=0.0145). While analysis of the NOR task revealed a significant reduction in latency to approach the novel versus familiar object on test day across all groups (F = 11.97, p=0.0013), no significant difference was seen between CBA and control groups. Interestingly, no main effects of OVX or interactive CBA/OVX effects were observed for either molecular or behavioral outcomes. We are currently considering alternative cognitive tasks that may better reveal CBA-associated cognitive deficits, as well as neuroadaptations in nuclear signaling downstream of MAPK activity. Together, these data suggest that chronic alcohol use results in profound changes in hippocampal plasticity, potentially facilitating cognitive decline and other CNS symptoms observed in PLWH. This research was supported by grant # T32AA007577 and #P60AA009803 from the NIAAA at the National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Progression of chronic infections to end-stage diseases and poor treatment results are frequently associated with alcohol abuse. Alcohol metabolism suppresses innate and adaptive immunity leading to increased viral load and its spread. In case of hepatotropic infections, viruses accelerate alcohol-induced liver hepatitis and fibrosis, thereby promoting end-stage outcomes, including cirrhosis and hepatocellular carcinoma (HCC). In this review, we concentrate on several unexplored aspects, which illustrate the combined effects of viral/bacterial infections and alcohol in disease development. Here, we overview alcohol-induced alterations implicated in immunometabolism as a central mechanism impacting metabolic homeostasis and viral pathogenesis in Simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection. Furthermore, in hepatocytes, both HIV-infection and alcohol activate oxidative stress to cause lysosomal dysfunction and leakage and apoptotic cell death, thereby increasing hepatotoxicity. In addition, we discuss the mechanisms of hepatocellular carcinoma and tumor signaling in hepatitis C virus (HCV)-infection. Finally, we analyze the studies aimed at reviewing and describing the immune derangements in hepatotropic viral infections for the development of novel targets and strategies to restore effective immunocompetency in alcohol-associated liver disease (ALD). In conclusion, alcohol exacerbates pathogenesis of viral infections, contributing to chronic course of infections and poor outcomes, but the mechanisms behind these events are virus-specific and depend on virus-alcohol interactions, which are not the same in various infections.

People living with HIV (PLWH) have increased prevalence of comorbid conditions including insulin resistance and at-risk alcohol use. Circulating microRNAs (miRs) may serve as minimally invasive indicators of pathophysiological states. We aimed to identify whether alcohol modulates circulating miR associations with measures of glucose/insulin dynamics in PLWH. PLWH ( n = 96; 69.8% males) enrolled in the Alcohol & Metabolic Comorbidities in PLWH: Evidence-Driven Interventions (ALIVE-Ex) study were stratified into negative phosphatidylethanol (PEth < 8 ng/mL, n = 42) and positive PEth (PEth ≥ 8 ng/mL, n = 54) groups. An oral glucose tolerance test (OGTT) was administered, and total RNA was isolated from fasting plasma to determine absolute miR expression. Circulating miRs were selected based on their role in skeletal muscle (miR-133a and miR-206), pancreatic β-cell (miR-375), liver (miR-20a), and adipose tissue (miR-let-7b, miR-146a, and miR-221) function. Correlation and multiple regression analyses between miR expression and adiponectin, 2 h glucose, insulin, and C-peptide values were performed adjusting for body mass index (BMI) category, age, sex, and viral load. miR-133a was negatively associated with adiponectin ( P = 0.002) in the negative PEth group, and miR-20a was positively associated with 2 h glucose ( P = 0.013) in the positive PEth group. Regression analyses combining miRs demonstrated that miR-133a ( P < 0.001) and miR-221 ( P = 0.010) together predicted adiponectin in the negative PEth group. miR-20a ( P < 0.001) and miR-375 ( P = 0.002) together predicted 2 h glucose in the positive PEth group. Our results indicate that associations between miRs and measures of glucose/insulin dynamics differed between PEth groups, suggesting that the pathophysiological mechanisms contributing to altered glucose homeostasis in PLWH are potentially modulated by alcohol use.

Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH), and the prevalence of at-risk alcohol use is higher among PLWH. Increased survival and aging of PLWH is associated with increased prevalence of metabolic comorbidities especially among menopausal women, and adipose tissue metabolic dysregulation may be a significant contributing factor. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome in a subset of simian immunodeficiency virus (SIV)-infected macaques of a longitudinal parent study. Quantitative discovery-based proteomics identified 1,429 differentially expressed proteins. Ingenuity Pathway Analysis (IPA) was used to calculate z-scores, or activation predictions, for functional pathways and diseases. Results revealed that protein changes associated with functional pathways centered around the “OmAT metaboproteome profile.” Based on z-scores, CBA did not affect functional pathways of metabolic disease but dysregulated proteins involved in adenosine monophosphate-activated protein kinase (AMPK) signaling and lipid metabolism. OVX-mediated proteome changes were predicted to promote pathways involved in glucose- and lipid-associated metabolic disease. Proteins involved in apoptosis, necrosis, and reactive oxygen species (ROS) pathways were also predicted to be activated by OVX and these were predicted to be inhibited by CBA. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administration produced larger metabolic and cellular effects, which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.

Alcohol misuse, directly or indirectly as a result of its metabolism, negatively impacts most tissues, including four with critical roles in energy metabolism regulation: the liver, pancreas, adipose, and skeletal muscle. Mitochondria have long been studied for their biosynthetic roles, such as ATP synthesis and initiation of apoptosis. However, current research has provided evidence that mitochondria participate in myriad cellular processes, including immune activation, nutrient sensing in pancreatic β-cells, and skeletal muscle stem and progenitor cell differentiation. The literature indicates that alcohol impairs mitochondrial respiratory capacity, promoting reactive oxygen species (ROS) generation and disrupting mitochondrial dynamics, leading to dysfunctional mitochondria accumulation. As discussed in this review, mitochondrial dyshomeostasis emerges at a nexus between alcohol-disrupted cellular energy metabolism and tissue injury. Here, we highlight this link and focus on alcohol-mediated disruption of immunometabolism, which refers to two distinct, yet interrelated processes. Extrinsic immunometabolism involves processes whereby immune cells and their products influence cellular and/or tissue metabolism. Intrinsic immunometabolism describes immune cell fuel utilization and bioenergetics that affect intracellular processes. Alcohol-induced mitochondrial dysregulation negatively impacts immunometabolism in immune cells, contributing to tissue injury. This review will present the current state of literature, describing alcohol-mediated metabolic and immunometabolic dysregulation from a mitochondrial perspective.

OBJECTIVE The present study examined interactions between simian immunodeficiency virus (SIV), chronic binge alcohol (CBA), and antiretroviral therapy (ART) on growth factor signaling, neuroinflammatory markers, viral loads (VL), and CD4+ cell counts. DESIGN Adult male rhesus macaques were administered CBA (13-14 g ethanol (EtOH)/kg per week) or sucrose (SUC) 3 months prior to SIVmac251 infection until the study endpoint. At viral setpoint, a subset of CBA/SIV+ and SUC/SIV+ macaques were randomized to receive daily ART (9-[2-Phosphonyl-methoxypropyly]adenine [PMPA] 20 mg/kg, 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), 30 mg/kg). Frontal cortex (FC) and basal ganglia (BG) were collected for gene and protein expression. METHODS Relationships between brain and plasma VL or CD4+ cell counts were determined using linear regression. Effects of SIV, CBA, and ART on markers of neuroinflammation and brain-derived neurotrophic factor (BDNF) signaling were determined by ANOVA and linear regression. RESULTS SIV increased FC and BG neuroinflammatory and glial cell gene expression (CX3CR1, B2M), and reduced FC protein kinase B phosphorylation. CBA decreased FC and BG tropomyosin receptor kinase B (TrkB) phosphorylation, and increased full-length TrkB (TrkB-FL) and SLC1A3 expression in FC and BG, respectively. ART suppressed plasma and brain VL, reduced neuroinflammatory gene expression in FC (IBA1, CX3CR1, and GFAP), and BG (CD74 and CD11s), and did not restore FC or BG BDNF signaling deficits. CONCLUSIONS Results show ART-mediated reduction in VL and neuroinflammatory gene expression, irrespective of CBA administration. ART did not attenuate SIV- and CBA-mediated BDNF signaling deficits, suggesting these deficits, despite effective neuroinflammation suppression, may explain CBA- and SIV-associated neurocognitive deficits. Therapeutics targeting growth factor signaling may be important adjuvants in treating HIV-associated neurocognitive decline.

On November 19th, 2021, the annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at Loyola University Chicago Health Sciences Campus in Maywood, Illinois. The 2021 meeting focused on how alcohol misuse is linked to immune system derangements, leading to tissue and organ damage, and how this research can be translated into improving treatment of alcohol-related disease. This meeting was divided into three plenary sessions: the first session focused on how alcohol misuse affects different parts of the immune system, the second session presented research on mechanisms of organ damage from alcohol misuse, and the final session highlighted research on potential therapeutic targets for treating alcohol-mediated tissue damage. Diverse areas of alcohol research were covered during the meeting, from alcohol's effect on pulmonary systems and neuroinflammation to epigenetic changes, senescence markers, and microvesicle particles. These presentations yielded a thoughtful discussion on how the findings can lead to therapeutic treatments for people suffering from alcohol-related diseases.

Our studies in chronic binge alcohol (CBA) treated simian immunodeficiency virus (SIV)-infected macaques and in people living with HIV (PLWH) show significant alterations in metabolic homeostasis. CBA promotes a profibrotic phenotype in adipose tissue and skeletal muscle (SKM) and decreases adipose-derived stem cell and myoblast differentiation, making adipose and SKM potential drivers in metabolic dysregulation. Furthermore, we have shown that the differential expression of microRNAs (miRs) in SKM contributes to impaired myoblast differentiation potential. Beyond modulation of intracellular responses, miRs can be transported in extracellular vesicles (EVs) to mediate numerous cellular responses through intercellular and interorgan communication. This study tested the hypothesis that CBA alters concentration and miR cargo of EVs derived from adipocytes and myotubes isolated from SIV-infected male macaques. Fourteen male rhesus macaques received either (CBA, 2.5g/kg/day) or sucrose (VEH) for 14.5 months. Three months following the initiation of CBA/VEH, all animals were infected with SIV

BACKGROUND: Myopathy affects nearly half of individuals with alcohol use disorder (AUD), and impaired skeletal muscle regenerative potential is a probable contributing factor. Previous findings from our laboratory indicate that chronic in vivo and in vitro ethanol treatment decrease myogenic potential of skeletal muscle myoblasts. Myogenesis, a highly coordinated process, requires shifts in cellular metabolic state allowing for myoblasts to proliferate and differentiate into mature myotubes. The objective of this study was to determine whether alcohol interferes with myoblast mitochondrial and glycolytic metabolism and impairs myogenic differentiation. METHODS: Myoblasts were isolated from vastus lateralis muscle excised from alcohol-naïve adult male (n=5) and female (n=5) rhesus macaques. Myoblasts were proliferated for 3 days (day 0 differentiation; D0) and differentiated for 5 days (D5) with or without 50 mM ethanol. Metabolism was assessed using a Mitochondrial Stress Test to measure oxygen consumption (OCR) and extracellular acidification (ECAR) rates at D0. Differentiation was examined at D5. Expression of mitochondrial and glycolytic genes and mitochondrial DNA (mtDNA) were measured at D0 and D5. RESULTS: Ethanol significantly (p

Unhealthy alcohol use is prevalent among persons living with HIV (PLWH). Aging and increased survival of PLWH on antiretroviral therapy (ART) are complicated by metabolic dysregulation and increased risk of insulin resistance (IR) and diabetes mellitus. The objective of this study was to determine the prevalence and association of IR with unhealthy alcohol use in adult in-care PLWH. A cross-sectional analysis of metabolic parameters and alcohol use characteristics was conducted in adult PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) Study. IR was estimated using homeostatic model assessment (HOMA-IR), triglyceride index, and McAuley index and beta cell function (HOMA-β). Alcohol use was assessed using Alcohol Use Disorders Identification Test (AUDIT)-C, 30-day timeline followback (TLFB), lifetime drinking history, and phosphatidylethanol (PEth) measures. A total of 351 participants, with a mean age [±standard deviation (SD)] of 48.1 ± 10.4 years, were included (69.6% male). Of these, 57% had an AUDIT-C score of 4 or greater, indicating unhealthy alcohol use. Mean body mass index (BMI) was 27.2 ± 7.0 kg/m(2), 36.4% met criteria for metabolic syndrome, and 14% were diagnosed with diabetes. After adjusting for education, race, BMI, smoking status, viral load, CD4 count, use of protease inhibitors, statins, or metformin; physical activity and diabetes diagnosis, HOMA-IR, and McAuley index were negatively associated with AUDIT-C, and HOMA-β cell function was negatively associated with AUDIT-C, PEth, and TLFB. Cross-sectional analysis of NOAH participants indicates that alcohol use is associated with decreased HOMA-β cell function, suggesting dysregulation of endocrine pancreatic function.

At-risk alcohol use is associated with multisystemic effects and end-organ injury, and significantly contributes to global health burden. Several alcohol-mediated mechanisms have been identified, with bioenergetic maladaptation gaining credence as an underlying pathophysiological mechanism contributing to cellular injury. This evidence-based review focuses on the current knowledge of alcohol-induced bioenergetic adaptations in metabolically active tissues: liver, cardiac and skeletal muscle, pancreas, and brain. Alcohol metabolism itself significantly interferes with bioenergetic pathways in tissues, particularly the liver. Alcohol decreases states of respiration in the electron transport chain, and activity and expression of respiratory complexes, with a net effect to decrease ATP content. In addition, alcohol dysregulates major metabolic pathways, including glycolysis, the tricarboxylic acid cycle, and fatty acid oxidation. These bioenergetic alterations are influenced by alcohol-mediated changes in mitochondrial morphology, biogenesis, and dynamics. The review highlights similarities and differences in bioenergetic adaptations according to tissue type, pattern of (acute vs. chronic) alcohol use, and energy substrate availability. The compromised bioenergetics synergizes with other critical pathophysiological mechanisms, including increased oxidative stress and accelerates cellular dysfunction, promoting senescence, programmed cell death, and end-organ injury.

At-risk alcohol use is a major contributor to the global health care burden and leads to preventable deaths and diseases including alcohol addiction, alcoholic liver disease, cardiovascular disease, diabetes, traumatic injuries, gastrointestinal diseases, cancers, and fetal alcohol syndrome. Excessive and frequent alcohol consumption has increasingly been linked to alcohol-associated tissue injury and pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal and in vitro models has elucidated the salient mechanisms involved in alcohol-induced tissue and organ injury. In some cases, these pathophysiological mechanisms are shared across organ systems. The major alcohol- and alcohol metabolite–mediated mechanisms include oxidative stress, inflammation and immunometabolic dysregulation, gut leak and dysbiosis, cell death, extracellular matrix remodeling, endoplasmic reticulum stress, mitochondrial dysfunction, and epigenomic modifications. These mechanisms are complex and interrelated, and determining the interplay among them will make it possible to identify how they synergistically or additively interact to cause alcohol-mediated multiorgan injury. In this article, we review the current understanding of pathophysiological mechanisms involved in alcohol-induced tissue injury.

Aims To assess whether binge drinking and heavy alcohol use are associated with increased sugar and fat consumption among a Southern cohort of people living with HIV (PWH). Methods This was a cross-sectional analysis of PWH enrolled in the New Orleans Alcohol use in HIV (NOAH) Study (n = 215). Binge and heavy drinking were identified through a 30-day Alcohol Timeline-Followback and dietary intake was assessed through a 24-hour dietary recall. Results Participants were 65.4% male, 83.3% Black, with a mean age of 49.2 ± 9.9. Heavy drinkers consumed more total calories than abstainers (P = 0.035) and low-to-moderate drinkers (P = 0.024), and binge drinkers consumed more calories than non-binge drinkers (P = 0.025). Binge and heavy drinkers had significantly higher intake of total and saturated fat in grams. However, substantially increased caloric intake among these participants led to non-significant associations for alcohol use with high total and saturated fat intake as a percent of total energy intake (%TEI). Binge drinkers had lower odds of consuming high sugar as a %TEI (odds ratio: 0.31 [0.14, 0.68]). Additionally, sugar intake predicted total and saturated fat intake, and this association was slightly higher among binge drinkers (total fat P-value: 0.12). Conclusions In this population of PWH, while binge and heavy drinking predicted higher caloric and fat intake in grams, binge drinkers were less likely to consume a high-sugar diet. This analysis suggests that interventions focused on reduced alcohol use may be especially beneficial in reducing metabolic disease burden in PWH if supplemented with information on incorporating lower energy-dense foods with reduced fat.

At-risk alcohol use is prevalent and increases dysglycemia among people living with human immunodeficiency virus (PLWH). Skeletal muscle (SKM) bioenergetic dysregulation is implicated in dysglycemia and type 2 diabetes. The objective of this study was to determine the relationship between at-risk alcohol, glucose tolerance, and SKM bioenergetic function in PLWH. Thirty-five PLWH (11 females, 24 males, age: 53 ± 9 yr, body mass index: 29.0 ± 6.6 kg/m2) with elevated fasting glucose enrolled in the ALIVE-Ex study provided medical history and alcohol use information [Alcohol Use Disorders Identification Test (AUDIT)], then underwent an oral glucose tolerance test (OGTT) and SKM biopsy. Bioenergetic health and function and mitochondrial volume were measured in isolated myoblasts. Mitochondrial gene expression was measured in SKM. Linear regression adjusting for age, sex, and smoking was performed to examine the relationship between glucose tolerance (2-h glucose post-OGTT), AUDIT, and their interaction with each outcome measure. Negative indicators of bioenergetic health were significantly ( P < 0.05) greater with higher 2-h glucose (proton leak) and AUDIT (proton leak, nonmitochondrial oxygen consumption, and bioenergetic health index). Mitochondrial volume was increased with the interaction of higher 2-h glucose and AUDIT. Mitochondrial gene expression decreased with higher 2-h glucose ( TFAM, PGC1B, PPARG, MFN1), AUDIT ( MFN1, DRP1, MFF), and their interaction ( PPARG, PPARD, MFF). Decreased expression of mitochondrial genes were coupled with increased mitochondrial volume and decreased bioenergetic health in SKM of PLWH with higher AUDIT and 2-h glucose. We hypothesize these mechanisms reflect poorer mitochondrial health and may precede overt SKM bioenergetic dysregulation observed in type 2 diabetes.

Aging people living with HIV (PLWH), especially postmenopausal women may be at higher risk of comorbidities associated with HIV, antiretroviral therapy (ART), hypogonadism, and at-risk alcohol use. Our studies in simian immunodeficiency virus (SIV)-infected male macaques demonstrated that chronic binge alcohol (CBA) reduced acute insulin response to glucose (AIRG), and at-risk alcohol use decreased HOMA-β in PLWH. The objective of this study was to examine the impact of ovariectomy (OVX) on glucose-insulin dynamics and integrity of pancreatic endocrine function in CBA/SIV-infected female macaques. Female macaques were administered CBA (12–15 g/kg/wk) or isovolumetric water (VEH) intragastrically. Three months after initiation of CBA/VEH administration, all macaques were infected with SIVmac251, and initiated on antiretroviral therapy (ART) 2.5 mo postinfection. After 1 mo of ART, macaques were randomized to OVX or sham surgeries ( n = 7 or 8/group), and euthanized 8 mo post-OVX (study endpoint). Frequently sampled intravenous glucose tolerance tests (FSIVGTT) were performed at selected time points. Pancreatic gene expression and islet morphology were determined at study endpoint. There was a main effect of CBA to decrease AIRG at Pre-SIV and study endpoint. There were no statistically significant OVX effects on AIRG ( P = 0.06). CBA and OVX decreased the expression of pancreatic markers of insulin docking and release. OVX increased endoplasmic stress markers. CBA but not OVX impaired glucose-insulin expression dynamics in SIV-infected female macaques. Both CBA and OVX altered integrity of pancreatic endocrine function. These findings suggest increased vulnerability of PLWH to overt metabolic dysfunction that may be exacerbated by alcohol use and ovarian hormone loss.

Aim This cross-sectional analysis of the New Orleans Alcohol Use in HIV (NOAH) study assesses whether current and lifetime alcohol use in people living with HIV (PLWH) are associated with greater liver disease and how hepatitis C-viral (HCV) co-infection (HIV/HCV+) modifies the association. Methods Alcohol use was measured by Lifetime Drinking History (LDH), a 30-day Timeline Followback calendar, the Alcohol Use Disorder Identification Test, and phosphatidylethanol. Liver disease was estimated by alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST platelet ratio-index (APRI), fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease-fibrosis score. Associations between alcohol consumption and liver disease were estimated with multivariable logistic regression. Models were adjusted for age, sex, body-mass index, hepatitis B and HIV viral load. Results Participants (N = 353) were majority male (69%) and black (84%) with a mean age of 48.3 ± 10 years. LDH was significantly associated with advanced liver fibrosis (FIB-4 aOR = 22.22 [1.22–403.72]) only among HIV/HCV+ participants with an LDH of 100–600 kg. HIV/HCV+ participants had a higher prevalence of intermediate and advanced liver disease markers than HIV/HCV− (P Conclusion Results indicate a greater association of current alcohol use with liver disease than lifetime alcohol use, which varied by HCV status. These findings stress the importance of reducing alcohol use in PLWH to decrease risk of liver disease and fibrosis.

BACKGROUND At-risk alcohol use is a common and costly form of substance misuse that is highly prevalent among people living with HIV (PLWH). The goal of the current analysis was to test the hypothesis that PLWH with at-risk alcohol use are more likely to meet the clinical criteria for prediabetes/diabetes than PLWH with low-risk alcohol use. METHODS A cross-sectional analysis was performed on measures of alcohol and glycemic control in adult PLWH (n = 105) enrolled in a prospective, interventional study (the ALIVE-Ex Study (NCT03299205)) that investigated the effects of aerobic exercise on metabolic dysregulation in PLWH with at-risk alcohol use. The Alcohol Use Disorders Identification Test (AUDIT), Timeline Followback, and phosphatidylethanol (PEth) level were used to measure alcohol use. Participants were stratified into low-risk (AUDIT score

Adipose tissue provides a rich and accessible source of multipotent stem cells, which are able to self-renew. These adipose-derived stem cells (ADSCs) provide a consistent ex vivo cellular system that are functionally like that of in vivo adipocytes. Use of ADSCs in biomedical research allows for cellular investigation of adipose tissue metabolic regulation and function. ADSC differentiation is necessary for adequate adipocyte expansion, and suboptimal differentiation is a major mechanism of adipose dysfunction. Understanding changes in ADSC differentiation is crucial to understanding the development of metabolic dysfunction and disease. The protocols described in this manuscript, when followed, will yield mature adipocytes that can be used for several in vitro functional tests to assess ADSC metabolic function, including but not limited to assays measuring glucose uptake, lipolysis, lipogenesis, and secretion. Rhesus macaques (Macaca mulatta) are physiologically, anatomically and evolutionarily similar to humans and as such, their tissues and cells have been used extensively in biomedical research and for development of treatments. Here, we describe ADSC isolation using fresh subcutaneous and omental adipose tissue obtained from 4- to 9-year old rhesus macaques. Adipose tissue samples are enzymatically digested in collagenase followed by filtration and centrifugation to isolate ADSCs from the stromal vascular fraction. Isolated ADSCs are proliferated in stromal media followed by approximately 14–21 days of differentiation using a cocktail of 0.5 ug/ml dexamethasone, 0.5 mM isobutyl methylxanthine, and 50 μM indomethacin in stromal media. Mature adipocytes are observed at approximately 14 days of differentiation. In this manuscript, we describe protocols for ADSC isolation, proliferation and differentiation in vitro. Although, we have focused on ADSCs from rhesus macaque adipose tissue, these protocols can be utilized for adipose tissue obtained from other animals with minimal adjustments.