Key points
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Australian researchers have found ‘switching off’ an enzyme called CaMKK2 in mice prevents diet-induced obesity, diabetes and fatty liver disease
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When CaMKK2 was deleted, the mice were shown to display healthier gene activity in their immune cells and fat tissue, and burned more energy overall
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The study establishes CaMKK2 as a therapeutic target for treating obesity and related metabolic disorders
An international team led by Monash University and Baylor College of Medicine, Texas, has found ‘switching off’ an enzyme called CaMKK2 in immune cells that drive inflammation prevents diet-induced obesity, diabetes and fatty liver disease.
CaMKK2 (Calcium/calmodulin-dependent protein kinase kinase 2) helps regulate how cells and the whole body use energy, and also controls inflammation driven by macrophages – a type of immune cell which lives in almost every tissue and sends signals to other cells to turn inflammation on or off.
In mice that were genetically altered so their macrophages lacked CaMKK2, the team behind the Molecular Metabolism study found the mice were protected against the harmful effects of a high-fat diet, including obesity and other metabolic diseases.
Dr John Scott from the Monash Institute of Pharmaceutical Sciences (MIPS), a lead author on the study, said the discovery shows CaMKK2 is a key player in how macrophages affect metabolism and inflammation.
“Obesity is linked to ongoing, low-level inflammation in key organs that control metabolism, like the liver, fat tissue and muscles, and this kind of inflammation plays a role in conditions such as insulin resistance and type 2 diabetes,” Dr Scott said.
“It’s widely accepted that a big driver of this process is the buildup of macrophages in these organs because when the body is under stress, such as from a high-fat diet, inflammatory macrophages switch to a faster but less efficient way of making energy.
“Our findings show that when the CaMKK2 gene is removed from certain immune cells (in this case, macrophages), fat tissue shifts its activity in a healthier direction. The genes in the fat start working in ways that support better metabolism and reduce harmful inflammation.
“In short, we’ve identified that CaMKK2 has direct control of regulating immune cell and whole-body metabolism, making it a promising new therapeutic target for treating obesity and related metabolic disorders.”
Professor Anthony Means, a co-lead author from the Baylor College of Medicine, led the first group to identify and clone CaMKK2.
“This study reveals that CaMKK2 acts as a molecular toggle to regulate macrophage metabolic flexibility, thus serving as a bridge between the metabolic and inflammatory pathways that coordinate and control the distinct functions of these cells,” Professor Means said.
Read the research paper: Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure.
DOI: https://doi.org/10.1016/j.molmet.2025.102250
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