Cover Story Current Issue

Brown adipose tissue (BAT) is a specialized fat tissue that is rich in mitochondria and promotes non-shivering thermogenesis by expressing the uncoupling protein 1 (UCP1). Unlike white adipose tissue, it burns calories to produce heat and therefore plays a key role in energy regulation and controlling metabolic health. Increasing energy expenditure by BAT activation is an intriguing therapeutic approach to combat the overwhelming obesity pandemic, either alone or to complement the current pharmacotherapy that mainly addresses energy intake based on the incretin-mimetic poly-agonist class of drugs. With this in mind it is not surprising that a lot of research was conducted to understand the molecular underpinnings of BAT regulation specifically addressing environmental cues. Cold exposure is the most powerful inducer of BAT activation leading to the upregulation of thermogenic gene program and adrenergic receptor-mediated activation of lipolysis and metabolism. BAT activation also occurs post-prandially, especially after acute overfeeding, to trigger diet-induced thermogenesis. However, this compensatory component of energy-expenditure is impaired during chronic overfeeding, a phenomenon that was termed adaptive thermogenesis, and is believed to further drive weight gain and obesity.

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Current Issue

Functional regulation of macrophages by Ces1d-mediated lipid signaling in immunometabolism

Long J. Shao, Fathima Elizondo, Feng Gao, Rabie Habib, ... Kai Sun

Functional regulation of macrophages by Ces1d-mediated lipid signaling in immunometabolism

 

Objective

Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.

Methods

A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d floxed/floxed, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d floxed/floxed, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and subjected to metabolic characterization. Adipose tissue, liver, and serum samples were analyzed histologically and biochemically. Endogenous macrophages and T cells from adipose tissue were isolated and analyzed for functional interactions by flow cytometry.

Results

Ces1d expression changes during the differentiation of monocytes into macrophages in both mice and humans. Loss of Ces1d causes larger lipid droplets, with increased accumulation of triacylglycerol (TAG) and diacylglycerol (DAG), and impaired lipid signaling in KO macrophages. Lipid dysregulation in macrophages triggers pro-inflammatory activation, enhancing migration, activation, and polarization toward an M1-like phenotype. The pro-inflammatory macrophages further promote CD3+CD8+ T cell accumulation in obese adipose tissue, which contributes to worsened metabolic disorders, including more severe fatty liver, increased local inflammation in adipose tissue, and impaired systemic glucose tolerance in KO mice on a high-fat diet.

Conclusions

This study demonstrates Ces1d is a crucial factor in maintaining lipid homeostasis in macrophages. Loss of Ces1d leads to metabolic dysregulation in macrophages and other immune cells during obesity.

 

Articles in Press

Functional regulation of macrophages by Ces1d-mediated lipid signaling in immunometabolism

Long J. Shao, Fathima Elizondo, Feng Gao, Rabie Habib, ... Kai Sun

Functional regulation of macrophages by Ces1d-mediated lipid signaling in immunometabolism

 

Objective

Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.

Methods

A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d floxed/floxed, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d floxed/floxed, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and subjected to metabolic characterization. Adipose tissue, liver, and serum samples were analyzed histologically and biochemically. Endogenous macrophages and T cells from adipose tissue were isolated and analyzed for functional interactions by flow cytometry.

Results

Ces1d expression changes during the differentiation of monocytes into macrophages in both mice and humans. Loss of Ces1d causes larger lipid droplets, with increased accumulation of triacylglycerol (TAG) and diacylglycerol (DAG), and impaired lipid signaling in KO macrophages. Lipid dysregulation in macrophages triggers pro-inflammatory activation, enhancing migration, activation, and polarization toward an M1-like phenotype. The pro-inflammatory macrophages further promote CD3+CD8+ T cell accumulation in obese adipose tissue, which contributes to worsened metabolic disorders, including more severe fatty liver, increased local inflammation in adipose tissue, and impaired systemic glucose tolerance in KO mice on a high-fat diet.

Conclusions

This study demonstrates Ces1d is a crucial factor in maintaining lipid homeostasis in macrophages. Loss of Ces1d leads to metabolic dysregulation in macrophages and other immune cells during obesity.

 

SAVE THE DATE!

13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

2024 impact factor: 6.6

You are what you eat

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