DiabetesJan 25, 2014

Cdc2-like kinase 2 reduces liver fat breakdown and ketone production by interfering with the PGC-1α and MED1 protein complex

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 3, 2026

Abstract

Liver-specific knockout of in mice fed a high-fat diet leads to increased fasting levels of blood ketone bodies.

Clk2 suppresses fatty acid oxidation and ketone body production during diet-induced obesity.
In lean mice, Clk2 protein levels are low during fasting but increase during feeding, while they remain elevated in obese mice.
Knockout of Clk2 in the liver results in a reduced respiratory exchange ratio and increased expression of genes involved in fatty acid oxidation and ketogenesis.
Clk2 acts in a cell-specific manner, influencing fatty acid utilization through its effects in hepatocytes.
Clk2 phosphorylates a protein that disrupts its interaction with another protein, leading to decreased activation of genes associated with fatty acid metabolism.

Simplified

Hepatic ketogenesis plays an important role in catabolism of fatty acids during fasting along with dietary lipid overload, but the mechanisms regulating this process remain poorly understood. Here, we show that (Clk2) suppresses fatty acid oxidation and ketone body production during diet-induced obesity. In lean mice, hepatic Clk2 protein is very low during fasting and strongly increased during feeding; however, in diet-induced obese mice, Clk2 protein remains elevated through both fed and fasted states. Liver-specific Clk2 knockout mice fed a high-fat diet exhibit increased fasting levels of blood ketone bodies, reduced respiratory exchange ratio, and increased gene expression of fatty acid oxidation and ketogenic pathways. This effect of Clk2 is cell-autonomous, because manipulation of Clk2 in hepatocytes controls genes and rates of fatty acid utilization. Clk2 phosphorylation of peroxisome proliferator-activated receptor γ coactivator (PGC-1α) disrupts its interaction with Mediator subunit 1, which leads to a suppression of PGC-1α activation of peroxisome proliferator-activated receptor α target genes in fatty acid oxidation and ketogenesis. These data demonstrate the importance of Clk2 in the regulation of fatty acid metabolism in vivo and suggest that inhibition of hepatic Clk2 could provide new therapies in the treatment of fatty liver disease.

Key numbers

N/A

Increase in Serum β-Hydroxybutyrate Levels

Observed in liver-specific knockout mice fed a high-fat diet.

N/A

Decrease in Liver Triglyceride Concentration

Noted in liver-specific knockout mice compared to controls.

N/A

Respiratory Exchange Ratio Decrease

Measured during fasting in knockout mice.

Full Text

We can’t show the full text here under this license.

View Full Text ↗

Cdc2-like kinase 2 reduces liver fat breakdown and ketone production by interfering with the PGC-1α and MED1 protein complex

Abstract

Key numbers

Full Text

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief

Abstract

Key numbers

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief