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Weight loss is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight-regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype male C57BL6/N mice were fed with high-fat diet for 10 wks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 wks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

SUMMARYThermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of ATP synthase. Here we provide evidence that mitochondrial phosphatidylethanolamine (PE) directly regulates UCP1-dependent proton conductance across IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PSD-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.

Background: The goal of the US Ending the HIV Epidemic (EHE) plan is to reduce HIV incidence by 75% by 2025 and 90% by 2030. This initiative will scale-up prevention and care activities in high-need areas like the Southeast United States. It is unknown what interventions, alone or in combination, will have the greatest impact towards reaching the EHE targets. Methods: We developed a stochastic HIV transmission model for men who have sex with men (MSM), calibrated to local surveillance estimates of HIV prevalence, PrEP utilization, and HIV care continuum levels in the Atlanta area. Model scenarios varied HIV screening rates relative to empirical levels, under two assumptions of how HIV-negative persons would be linked to PrEP initiation, and also considered relative improvements to HIV care linkage and care retention for those screening positive. We estimated both the proportion of cumulative infections averted over 10 years and the reduction in incidence rates relative to EHE targets. Results: A ten-fold relative increase in HIV screening rates (to approximately biannual screening for black and Hispanic MSM and quarterly for white MSM) would lead to 41% of infections averted under the assumption of integrated linkage to PrEP, with prevention through both increased PrEP coverage and increased HIV viral suppression. At the same relative increase in screening but under the assumption of no PrEP linkage, only 9.9% of infections would be averted, with prevention only through increased viral suppression. Improvements to HIV care retention would avert 33.5% of infections if retention rates were improved 10-fold. If both screening and retention were jointly improved 10-fold, 66.6% and 48.5% of cumulative infections would be averted under assumptions of PrEP linkage and no-linkage, respectively. Under the joint 10-fold PrEP-linked scenario, it would take 7.3 years to meet the 75% EHE target and 30.4 years to meet the 90% target for MSM in Atlanta. Conclusions: Interventions to improve HIV screening linked with PrEP for those screening negative, and HIV care retention would have a substantial impact on HIV prevention through reduction of HIV acquisition and transmission rates. However, additional interventions beyond these substantial improvements to HIV screening, PrEP coverage, and HIV care retention will be necessary to reach the EHE target of a 90% reduction in incidence for Atlanta MSM by 2030.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analyses of primary myocytes from lean insulin-sensitive (LN) and obese insulin-resistant (OB) individuals revealed several species of lysophospholipids (lyso-PL) that were differentially-abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with greater insulin sensitivityin vivoand insulin-stimulated skeletal muscle glucose uptakeex vivo. Absence of LPCAT3 reduced phospholipid packing of the cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.