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Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations. A study of blood lipids in two cohorts using a new replication test, ScreenDMT, finds that people with lower BMI have higher levels of linoleic acid diols 12,13-diHOME and 9,10-diHOME, which upregulate adipocyte calcium influx. [ABSTRACT FROM AUTHOR]

Opsin3 (Opn3) is a transmembrane heptahelical G protein–coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin resistance. At the cellular level, Opn3-KO brown adipocytes cultured in darkness had decreased glucose uptake and lower nutrient-induced mitochondrial respiration than wild-type (WT) cells. Light exposure promoted mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3's putative G protein–binding domain also exhibited a reduction in glucose uptake and mitochondrial respiration in darkness. Using RNA-sequencing, we identified several novel light-sensitive and Opn3-dependent molecular signatures in brown adipocytes. Importantly, direct exposure of brown adipose tissue (BAT) to light in living mice significantly enhanced thermogenic capacity of BAT, and this effect was diminished in Opn3-KO animals. These results uncover a previously unrecognized cell-autonomous, light-sensing mechanism in brown adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and mitochondrial respiration. Our work also provides a molecular basis for developing light-based treatments for obesity and its related metabolic disorders. Brown adipose tissue plays a pivotal role in energy homeostasis and serves as a metabolic sink for glucose and fatty acid. This study demonstrates a novel light-sensing mechanism in mice via the photoreceptor Opsin3 that regulates fuel utilization and mitochondrial activity of brown adipocytes. [ABSTRACT FROM AUTHOR]

Recent studies suggest that, even within a single adipose depot, there may be distinct subpopulations of adipocytes. To investigate this cellular heterogeneity, we have developed multiple conditionally immortalized clonal preadipocyte lines from white adipose tissue of mice. Analysis of these clones reveals at least three white adipocyte subpopulations. These subpopulations have differences in metabolism and differentially respond to inflammatory cytokines, insulin, and growth hormones. These also have distinct gene expression profiles and can be tracked by differential expression of three marker genes: Wilms' tumor 1, transgelin, and myxovirus 1. Lineage tracing analysis with dual‐fluorescent reporter mice indicates that these adipocyte subpopulations have differences in gene expression and metabolism that mirror those observed in the clonal cell lines. Furthermore, preadipocytes and adipocytes from these subpopulations differ in their abundance in different fat depots. Thus, white adipose tissue, even in a single depot, is comprised of distinct subpopulations of white adipocytes with different physiological phenotypes. These differences in adipocyte composition may contribute to the differences in metabolic behavior and physiology of different fat depots. Synopsis: While differences between white, beige and brown adipose tissues are relatively well studied, heterogeneity within white adipocytes remains unclear. Here, combined profiling and lineage tracing analyses identify distinct subpopulations of white fat cells even in a single pad, possibly explaining discrepant metabolic behavior and physiology of different depots. Immortalized mouse preadipocyte cell lines display three white adipocyte subpopulations with differential gene expression and markers.Adipocyte subpopulations differ in energy metabolism and response to inflammatory cytokines, insulin, and growth hormones.The adipocyte subpopulations can be distinguished by expression of Wilms' tumor 1, transgelin, and myxovirus 1.Preadipocytes and adipocytes from these subpopulations show varying abundance in different fat depots in vivo. Gene expression profiling and lineage tracing reveal that white fat tissue in mouse is comprised of multiple adipocyte subtypes with distinct metabolic profiles. [ABSTRACT FROM AUTHOR]