Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 Regulates Hepatic Fuel Metabolism

Authors

Brittany A Stork
Adam Dean
Andrea R Ortiz
Pradip Saha
Nagireddy Putluri
Maricarmen D Planas-Silva
Iqbal Mahmud
Kimal Rajapakshe
Cristian Coarfa
Stefan Knapp
Philip L Lorenzi
Bruce E Kemp
Benjamin E Turk
John W Scott
Anthony R Means
Brian York

Publication Date

8-1-2022

Journal

Molecular Metabolism

DOI

10.1016/j.molmet.2022.101513

PMID

35562082

PMCID

PMC9157561

PubMedCentral® Posted Date

5-11-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Fatty Acids, Glucose, Insulin Resistance, Mice, Insulin resistance, Glucose metabolism, Fatty acid metabolism, Peroxisome, Kinase signaling

Abstract

OBJECTIVE: The liver is the primary internal metabolic organ that coordinates whole body energy homeostasis in response to feeding and fasting. Genetic ablation or pharmacological inhibition of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) has been shown to significantly improve hepatic health and peripheral insulin sensitivity upon overnutrition with high fat diet. However, the precise molecular underpinnings that explain this metabolic protection have remained largely undefined.

METHODS: To characterize the role of CaMKK2 in hepatic metabolism, we developed and challenged liver-specific CaMKK2 knockout (CaMKK2

RESULTS: Consistent with previous findings, we show that hepatic CaMKK2 ablation significantly improves indices of peripheral insulin sensitivity. Mechanistically, we found that CaMKK2 phosphorylates and regulates GAPDH to promote glucose metabolism and PEX3 to blunt peroxisomal fatty acid catabolism in the liver.

CONCLUSION: CaMKK2 is a central metabolic fuel sensor in the liver that significantly contributes to whole body systems metabolism.