Language
English
Publication Date
11-1-2025
Journal
Molecular Metabolism
DOI
10.1016/j.molmet.2025.102250
PMID
40945690
PMCID
PMC12493246
PubMedCentral® Posted Date
9-11-2025
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Animals, Obesity, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Insulin Resistance, Energy Metabolism, Mice, Diet, High-Fat, Male, Macrophages, Mice, Inbred C57BL, Adipose Tissue, Liver, Mice, Knockout, Inflammation, Myeloid Cells, Fatty Liver, Kinase signaling, Inflammation, Insulin resistance, Glucose homeostasis, Liver steatosis
Published Open-Access
yes
Recommended Citation
Ortiz, Andrea R; Nay, Kevin; Stork, Brittany A; et al., "Myeloid-Specific CAMKK2 Deficiency Protects Against Diet-Induced Obesity and Insulin Resistance by Rewiring Metabolic Gene Expression and Enhancing Energy Expenditure" (2025). Faculty and Staff Publications. 4366.
https://digitalcommons.library.tmc.edu/baylor_docs/4366