Frontline Science: Rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages

Obesityâ related changes in adipose tissue leukocytes, in particular adipose tissue macrophages (ATMs) and dendritic cells (ATDCs), are implicated in metabolic inflammation, insulin resistance, and altered regulation of adipocyte function. We evaluated stromal cell and white adipose tissue (WAT) expansion dynamics with high fat diet (HFD) feeding for 3â 56 days, quantifying ATMs, ATDCs, endothelial cells (ECs), and preadipocytes (PAs) in visceral epididymal WAT and subcutaneous inguinal WAT. To better understand mechanisms of the early response to obesity, we evaluated ATM proliferation and lipid accumulation. ATMs, ATDCs, and ECs increased with rapid WAT expansion, with ATMs derived primarily from a CCR2â independent resident population. WAT expansion stimulated proliferation in resident ATMs and ECs, but not CD11c+ ATMs or ATDCs. ATM proliferation was unperturbed in Csf2â and Rag1â deficient mice with WAT expansion. Additionally, ATM apoptosis decreased with WAT expansion, and proliferation and apoptosis reverted to baseline with weight loss. Adipocytes reached maximal hypertrophy at 28 days of HFD, coinciding with a plateau in resident ATM accumulation and the appearance of lipidâ laden CD11c+ ATMs in visceral epididymal WAT. ATM increases were proportional to tissue expansion and adipocyte hypertrophy, supporting adipocyteâ mediated regulation of resident ATMs. The appearance of lipidâ laden CD11c+ ATMs at peak adipocyte size supports a role in responding to ectopic lipid accumulation within adipose tissue. In contrast, ATDCs increase independently of proliferation and may be derived from circulating precursors. These changes precede and establish the setting in which largeâ scale adipose tissue infiltration of CD11c+ ATMs, inflammation, and adipose tissue dysfunction contributes to insulin resistance.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142947/1/jlb10097_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142947/2/jlb10097.pd

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The role of long noncoding RNAs in cancer metastasis

Signaling pathways are tightly controlled systems that regulate the appropriate timing of gene expression required for the differentiation of cells down a particular lineage essential for proper tissue development. Proliferation, apoptosis and metabolic pathways are just a few examples of the signaling pathways that require fine-tuning, so as to control the proper development of a particular tissue type or organ system. An estimated 70% of the genome is actively transcribed, only 2% of which codes for known protein-coding genes. Long noncoding RNAs (lncRNAs) in particular, are a large and diverse class of RNAs > 200 nucleotides in length, and not translated into protein. lncRNAs are essential transcriptional and post-transcriptional regulators that control the expression of genes in a spatial, temporal, and cell context-dependent manner. The aberrant expression of lncRNAs is therefore linked with a number of chronic diseases including cardiac dysfunction, diabetes, and cancer. In this review, we highlight the specific role lncRNAs have in promoting the metastatic cascade across a number of epithelial cancer models

A Model for Gastric Banding in the Treatment of Morbid Obesity: The Effect of Chronic Partial Gastric Outlet Obstruction on Esophageal Physiology

OBJECTIVE: This work establishes an animal model for nonadjustable gastric banding and characterizes the effect of gastric banding on esophageal physiology. SUMMARY BACKGROUND DATA: Obstruction at the esophagogastric junction (EGJ) results in esophageal dilation and aperistalsis. Although laparoscopic gastric banding as a primary treatment of morbid obesity has been widely accepted, the effects of this therapy on esophageal function remain unknown. METHODS: Twenty-five opossums were randomly divided into sham (n = 5), EGJ band (n = 5), and gastric band (n = 15) groups. Gastric and EGJ bands were surgically placed, and esophageal manometry was performed prebanding, at 2-week intervals during the banding period (up to 14 weeks), and 2 and 4 weeks after band removal. RESULTS: Manometric measures were equivalent prior to banding in all groups. There were no changes in LES or esophageal pressures during the study period in the sham group. During banding, there was a 36% decrease in baseline mean resting lower esophageal sphincter pressure in the gastric band group (P = 0.003). Mean distal esophageal peristaltic pressure decreased from baseline by 36% in gastric band animals (P < 0.001). The incidence of esophageal motility disorder during the study period for sham, EGJ band, and gastric band groups, was 2.9%, 42.1%, and 31.3%, respectively (P = 0.001, P = 0.381, pairwise comparisons of gastric band vs. sham and gastric band versus EGJ groups, respectively). Immediately prior to band removal, the probability of an abnormal peristaltic sequence with each swallow was 1%, 38%, and 16% for sham, EGJ, and gastric band groups, respectively (P < 0.005, pairwise comparisons of band groups with sham). CONCLUSIONS: Nonadjustable gastric banding results in impaired esophageal body motility, a reduction in esophageal peristaltic pressure, and a reduction in resting lower esophageal sphincter pressure. These findings suggest that gastric banding causes esophageal outlet obstruction and subsequent decompensation of peristaltic function as well as a compromise of the native antireflux mechanism