José Orlando Alemán

Monoacylglycerol (MAG) is an important bioactive lipid metabolite/intermediate, playing crucial roles in energy homeostasis and cellular signaling. This review explores MAG’s chemical structure, classification, and metabolic pathways. We also discuss the emerging evidence for MAG as a signaling molecule, with particular emphasis on their interactions with cannabinoid receptor 1 and cannabinoid receptor 2 and G-protein-coupled receptor 119. We focus on examining the diverse and tissue-specific functions of MAG in the context of metabolic diseases, including the roles of MAG in nutrient absorption, appetite regulation, obesity, glucose homeostasis, and lipid metabolism. Furthermore, we address therapeutic approaches in modulating MAG metabolism and challenges in development, considering the complexity of targeting peripheral tissues. This review provides insights into the multifaceted roles of MAG in metabolic health and disease, paving the way for novel therapeutic strategies in the management of metabolic disorders.

Background: Automated identification of postprandial glucose responses (PPGR) from continuous glucose monitoring (CGM) profiles may detect early dysglycemia in people without diabetes. However, no standard approach for this task currently exists. Methods: We developed a wavelet transform-based AI algorithm to identify PPGRs using only CGM data. The algorithm was evaluated on a public CGM dataset of 25 normoglycemic adults and three independent validation cohorts (n = 65 total) with a mix of normoglycemia and prediabetes. Performance metrics included mealtime prediction error and total and incremental areas under the PPGR curve (tAUC and iAUC, respectively). Associations between AI-derived PPGR parameters and clinical markers such as HbA1c and fasting glucose were also examined. Results: In the public dataset, 25 participants (age 40 ± 14 years, BMI 26 ± 6 kg/m ² , HbA1c 5.4 ± 0.4%) provided 3 ± 1 days of paired CGM data and ground-truth mealtimes. The algorithm predicted PPGR start time with a median error of 10 [IQR: 4, 19] minutes relative to ground-truth mealtimes. Postprandial glucose response parameters including tAUC and iAUC derived using ground-truth mealtimes versus AI-predicted mealtime were similar (all P > .1), indicating the algorithm faithfully captured PPGR characteristics. In adjusted analysis, AI-derived PPGR iAUC was independently associated with laboratory markers including HbA1c (β = 0.57 [95% CI: 0.19, 0.95], P = .006) and fasting glucose (β = 0.52 [95% CI: 0.12, 0.92], P = .013). Algorithm performance remained consistent across the three validation cohorts. Conclusions: The wavelet AI algorithm accurately identified PPGRs from CGM data in people without diabetes, offering a novel automated approach to monitor early signs of postprandial dysglycemia in this population.

BACKGROUND: Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell (EC) barrier. This process allows the heart to obtain fatty acids, its chief source of energy, and apoB-containing lipoproteins to cross the arterial endothelial barrier, leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial TRLs (triglyceride-rich lipoproteins) as an independent risk factor for cardiovascular disease. We explored how chylomicrons affect ECs and transfer their fatty acids across the EC barrier. METHODS: We had reported that media from chylomicron-treated ECs lead to lipid droplet formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid, and microRNA content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of SR-BI (scavenger receptor-BI) altered these responses. In addition, using chylomicrons labeled with [ ¹³ C]oleate, we studied the uptake and release of this labeled by ECs. RESULTS: Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage lipid droplet accumulation. The EVs contained little free fatty acids and triglycerides, but abundant phospholipids and diacylglycerols. In concert with this, [ ¹³ ]C labeled chylomicron triglycerides exited ECs primarily in phospholipids. EVs from chylomicron-treated versus untreated ECs were larger, more abundant, and contained specific microRNAs. Treatment of macrophages and naive ECs with media from chylomicron-treated ECs increased expression of inflammatory genes. CONCLUSIONS: EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. Fatty acids within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition.

Background: Throughout the course of the COVID-19 pandemic, clinicians recognized that individuals with metabolic syndrome, including elevated body mass index (BMI) and type 2 diabetes, have increased clinical care requirements and worsened outcomes during COVID-19 infection. With the availability of COVID-19 vaccines, it was unknown whether vaccination could mitigate the clinical outcomes among patients with metabolic syndrome. In this study, we sought to determine whether BMI and hemoglobin A1c are associated with a risk of breakthrough infection and increased clinical needs among patients who have been fully vaccinated against COVID-19. Methods: We conducted a retrospective cohort study of patients in the Veterans Affairs healthcare system who were vaccinated against COVID-19 between 1 December 2020 and 22 August 2021. We sampled a random subset of 549,344 patients from a total of over 1 million de-identified patients greater than age 18 who were vaccinated between 1 December 2020 and 22 August 2021, without a prior positive COVID-19 test in the VA healthcare system data warehouse. The primary study outcomes were breakthrough COVID-19 infections after vaccination and hospitalization due to breakthrough COVID-19 infections. Results: We identified 480,129 patients with available BMI and hemoglobin A1c data; of these, all had data available for the covariates of race, ethnicity, sex, and age, and 467,283 had data available for district as well. Adjusting for those covariates, Cox proportional hazards modeling for time from vaccination until breakthrough infection demonstrated that higher BMI (HR per unit 1.015, p < 0.001) and hemoglobin A1c were associated with an increased risk of infection (HR per unit 1.063, p < 0.001). The number of patients from this set who developed breakthrough infections within the study period was 8903 (9146 if those with missing district data were included). The average age of fully vaccinated patients with breakthrough COVID-19 infection within six months of full vaccination was 64.5. The average BMI was 31.2 ± 6.2 and the average A1c was 6.34 ± 1.5. Adjusting for the above covariates, multivariable logistic regression trends towards significance, with an increased risk of hospitalization due to breakthrough COVID-19 infection with increased BMI (HR per unit 1.010, p = 0.052), and was statistically significant for increased hemoglobin A1c (HR per unit 1.150, p < 0.010). Conclusions: This study identifies BMI and hemoglobin A1c as risk factors for breakthrough COVID-19 infection among fully vaccinated patients in the US veteran population.

Objective: This study examined racial and ethnic differences in percent total weight loss (%TWL) and glycemic improvement following sleeve gastrectomy (SG) and explored the role of socioeconomic and psychosocial factors in postsurgical outcomes.Methods: This longitudinal study included patients who underwent SG between 2017 and 2020, with follow‐up visits over 24 months.Results: Non‐Hispanic Black (NHB) participants had lower %TWL at 3, 12, and 24 months compared with Hispanic (H) and non‐Hispanic White (NHW) participants. Fat mass index was initially lower in NHB, with smaller reductions over time and significant group differences persisting at 24 months. NHB participants had higher baseline fat‐free mass index values; by 24 months, fat‐free mass index values were lower in H participants. Hemoglobin A1c decreased across all groups but remained consistently higher in NHB and H compared with NHW at 24 months. NHB participants reported higher perceived discrimination, sleep disturbance, and perceived stress than H and NHW participants at all time points. Employment status predicted %TWL at 12 months. There was a significant interaction between race and ethnicity and employment status observed at 12 and 24 months, suggesting that employment‐related disparities could impact surgical outcomes.Conclusions: NHB participants experienced less favorable outcomes following SG, emphasizing the need for tailored interventions addressing socioeconomic and psychosocial disparities.

Background: Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell barrier. This process allows the heart to obtain fatty acids (FAs), its chief source of energy and apolipoprotein B (apoB)-containing lipoproteins to cross the arterial endothelial barrier leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial triglyceride-rich lipoproteins (TRLs) as an independent risk factor for cardiovascular disease (CVD). We explored how chylomicrons affect ECs and transfer their FAs across the EC barrier. Methods: We had reported that media from chylomicron-treated ECs leads to lipid droplet (LD) formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid and microRNA (miR) content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of scavenger receptor-BI (SR-BI) altered these responses. In addition, using chylomicrons labeled with [ ¹³ C]oleate, we studied the uptake and release of this labed by ECs. Results: Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage LD accumulation. The EVs contained little free fatty acids and triglyceride, but abundant phospholipids and diacylglycerols. In concert with this, [ ¹³ ]C labeled chylomicron triglycerides exited ECs primarily in phospholipids. EVs from chylomicron treated versus untreated ECs were larger, more abundant, and contained specific miRs. Treatment of macrophages and naïve ECs with media from chylomicron-treated ECs increased expression of inflammatory genes. Conclusions: EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. FAs within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition.