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The pancreas is a mixed gland primarily composed of exocrine tissue, which secretes digestive enzymes into the digestive tract, and an endocrine component organized into small clusters known as islets of Langerhans, constituting approximately 1% of the pancreatic mass. Each adult islet contains an average of 1,500 cells, including beta-, alpha- and delta-cells, which produce and secrete insulin (INS), glucagon (GCG), and somatostatin (SST) respectively. The destruction of insulin-producing beta-cells or the defective insulin secretion give rise to type 1 and type 2 diabetes mellitus, respectively. These chronic metabolic disorders are characterized by the dysregulation of glucose homeostasis. 

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Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure

Andrea R. Ortiz, Kevin Nay, Brittany A. Stork, Adam M. Dean, ... John W. Scott

Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure

Objective

Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.

Methods

Mice with myeloid-specific deletion of Camkk2 were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.

Results

Myeloid-specific Camkk2 deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.

Conclusions

Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.

Articles in Press

Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure

Andrea R. Ortiz, Kevin Nay, Brittany A. Stork, Adam M. Dean, ... John W. Scott

Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure

Objective

Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.

Methods

Mice with myeloid-specific deletion of Camkk2 were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.

Results

Myeloid-specific Camkk2 deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.

Conclusions

Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.

2022 impact factor: 6.6

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