Angiopoietin-like 4 (Angptl4) is a secreted protein modulating triacylglycerol homeostasis. Its transcription is induced by glucocorticoids, which act to elevate circulating Angptl4 levels during fasting. In investigating the role of Angptl4 in glucocorticoid action, we identified that in addition to its known ability to inhibit lipoprotein lipase, Angptl4 stimulates intracellular adipocyte lipolysis. Fatty acid release by murine adipocytes following fasting or treatment with glucocorticoids or catecholamines is highly Angptl4-dependent. In fact, Angptl4 can directly stimulate cAMP-dependent PKA signaling and lipolysis when added to adipocytes. Here, we detail this novel Angptl4-dependent lipolytic regulatory mechanism and discuss its physiological and therapeutic implications.

Purpose of review

The current review provides an update on secreted factors and mechanisms that promote a thermogenic program in beige adipocytes, and their potential roles as therapeutic targets to fight obesity.

Recent findings

We outline recent studies revealing unrecognized mechanisms controlling beige adipocyte physiology, and summarize in particular those that underlie beige thermogenesis independently of classical uncoupling. We also update strategies aimed at fostering beige adipogenesis and white-to beige adipocyte conversion. Finally, we summarize newly identified endogenous secreted factors that promote the thermogenic activation of beige adipocytes and discuss their therapeutic potential.

Summary

The identification of novel endogenous factors that promote beiging and regulate beige adipocyte-specific physiological pathways opens up new avenues for therapeutic engineering targeting obesity and related metabolic disorders.

Purpose of review

The current review provides an update on secreted factors and mechanisms that promote a thermogenic program in beige adipocytes, and their potential roles as therapeutic targets to fight obesity.

Recent findings

We outline recent studies revealing unrecognized mechanisms controlling beige adipocyte physiology, and summarize in particular those that underlie beige thermogenesis independently of classical uncoupling. We also update strategies aimed at fostering beige adipogenesis and white-to beige adipocyte conversion. Finally, we summarize newly identified endogenous secreted factors that promote the thermogenic activation of beige adipocytes and discuss their therapeutic potential.

Summary

The identification of novel endogenous factors that promote beiging and regulate beige adipocyte-specific physiological pathways opens up new avenues for therapeutic engineering targeting obesity and related metabolic disorders.

PAGE 8455: There was an error in the text. On page 8455, in the first full paragraph, “the C terminus of Angptl4 alone can inhibit Lpl” should be “the N terminus of Angptl4 alone can inhibit Lpl.”

Surgery can induce cognitive decline, a risk that increases with advancing age. In rodents, postoperative cognitive decline (POCD) is associated with the inflammatory activation of hippocampal microglia. To examine the role of microglia in POCD, we inhibited the colony-stimulating factor 1 receptor (CSF1R) in adult mice, effectively depleting CNS microglia. Surgical trauma (tibial fracture) reduced the ability of mice to remember a conditioned response learned preoperatively, a deficit more pronounced and persistent in mice with diet-induced obesity (DIO). Whereas microglial depletion by itself did not affect learning or memory, perioperative microglial depletion remarkably protected mice, including those with DIO, from POCD. This protection was associated with reduced hippocampal levels of inflammatory mediators, abrogation of hippocampal recruitment of CCR2+ leukocytes, and higher levels of circulating inflammation-resolving factors. Targeting microglia may thus be a viable strategy to mitigate the development of POCD, particularly in those with increased vulnerability.

The final step of triacylglycerol synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferases (DGATs). We have previously shown that ApoE-/-Dgat1-/- mice are protected from developing atherosclerosis in association with reduced foam cell formation. However, the role of DGAT1, specifically in myeloid and other hematopoietic cell types, in determining this protective phenotype is unknown. To address this question, we reconstituted the bone marrow of irradiated Ldlr-/-mice with that from wild-type (WT→ Ldlr-/-) and Dgat1-/-(Dgat1-/-→ Ldlr-/-) donor mice. We noted that DGAT1 in the hematopoietic compartment exerts a sex-specific effect on systemic cholesterol homeostasis. However, both male and female Dgat1-/-→ Ldlr-/-mice had higher circulating neutrophil and lower lymphocyte counts than control mice, suggestive of a classical inflammatory phenotype. Moreover, specifically examining the aortae of these mice revealed that Dgat1-/-→ Ldlr-/-mice have atherosclerotic plaques with increased macrophage content. This increase was coupled to a reduced plaque collagen content, leading to a reduced collagen-to-macrophage ratio. Together, these findings point to a difference in the inflammatory contribution to plaque composition between Dgat1-/-→ Ldlr-/-and control mice. By contrast, DGAT1 deficiency did not affect the transcriptional responses of cultured macrophages to lipoprotein treatment in vitro, suggesting that the alterations seen in the plaques of Dgat1-/-→ Ldlr-/-mice in vivo do not reflect a cell intrinsic effect of DGAT1 in macrophages. We conclude that although DGAT1 in the hematopoietic compartment does not impact the overall lipid content of atherosclerotic plaques, it exerts reciprocal effects on inflammation and fibrosis, two processes that control plaque vulnerability.

Objective

Using the newly created University of California (UC) Health Data Warehouse, we present the first study to analyze antihyperglycemic treatment utilization across the five large UC academic health systems (Davis, Irvine, Los Angeles, San Diego, and San Francisco).

Research design and methods

This retrospective analysis used deidentified electronic health records (EHRs; 2014-2019) including 97,231 patients with type 2 diabetes from 1,003 UC-affiliated clinical settings. Significant differences between health systems and individual providers were identified using binomial probabilities with cohort matching.

Results

Our analysis reveals statistically different treatment utilization patterns not only between health systems but also among individual providers within health systems. We identified 21 differences among health systems and 29 differences among individual providers within these health systems, with respect to treatment intensifications within existing guidelines on top of either metformin monotherapy or dual therapy with metformin and a sulfonylurea. Next, we identified variation for medications within the same class (e.g., glipizide vs. glyburide among sulfonylureas), with 33 differences among health systems and 86 among individual providers. Finally, we identified 2 health systems and 55 individual providers who more frequently used medications with known cardioprotective benefits for patients with high cardiovascular disease risk, but also 1 health system and 8 providers who prescribed such medications less frequently for these patients.

Conclusions

Our study used cohort-matching techniques to highlight real-world variation in care between health systems and individual providers. This demonstrates the power of EHRs to quantify differences in treatment utilization, a necessary step toward standardizing precision care for large populations.