Cover Story Current Issue

Weaning involves a dietary switch in mammals, progressively decreasing the reliance on the consumption of a fat-rich milk diet in favour of a carbohydrate-rich diet. Metabolic adaptation to this shift in macronutrient consumption is characterized by reduced hepatic gluconeogenesis, increased liver glycogen content, and changes in lipid metabolism. Such metabolic changes are supported by various nutritional, hormonal, and neuronal factors. Dietary changes during weaning are shown to drive β-cell proliferation and maturation, which is important for the optimal endocrine function of the pancreas. A switch from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5′-adenosine monophosphate-activated protein kinase (AMPK) was found critical for functional maturation of β-cells. Furthermore, changes in the macronutrient composition during the weaning process drive alterations in the gut microbiome, which is essential for the development of immune tolerance. The major calcium absorption pathway also changes during weaning, from the paracellular pathway during the suckling stage to the vitamin D dependent transcellular pathway post-weaning. However, the factors that regulate these post-weaning metabolic adaptations are not fully understood.

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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

12th Helmholtz 
Diabetes Conference 
22-24. Sep, Munich

2022 impact factor: 6.6

You are what you eat

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