Loss of Par-1a/MARK3/C-TAK1 kinase leads to reduced adiposity, resistance to hepatic steatosis, and defective gluconeogenesis.

Abstract

Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs, and mammals. The mammalian Par-1 family consists of four members. Knockout studies of mice implicate Par-1b/MARK2/EMK in regulating fertility, immune homeostasis, learning, and memory as well as adiposity, insulin hypersensitivity, and glucose metabolism. Here, we report phenotypes of mice null for a second family member (Par-1a/MARK3/C-TAK1) that exhibit increased energy expenditure, reduced adiposity with unaltered glucose handling, and normal insulin sensitivity. Knockout mice were protected against high-fat diet-induced obesity and displayed attenuated weight gain, complete resistance to hepatic steatosis, and improved glucose handling with decreased insulin secretion. Overnight starvation led to complete hepatic glycogen depletion, associated hypoketotic hypoglycemia, increased hepatocellular autophagy, and increased glycogen synthase levels in Par-1a(-/-) but not in control or Par-1b(-/-) mice. The intercrossing of Par-1a(-/-) with Par-1b(-/-) mice revealed that at least one of the four alleles is necessary for embryonic survival. The severity of phenotypes followed a rank order, whereby the loss of one Par-1b allele in Par-1a(-/-) mice conveyed milder phenotypes than the loss of one Par-1a allele in Par-1b(-/-) mice. Thus, although Par-1a and Par-1b can compensate for one another during embryogenesis, their individual disruption gives rise to distinct metabolic phenotypes in adult mice.

• Authors: Jochen K Lennerz, Jonathan B Hurov, Lynn S White, Katherine T Lewandowski, Julie L Prior, G James Planer, Robert W Gereau 4th, David Piwnica-Worms, Robert E Schmidt, Helen Piwnica-Worms
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 30 Issue 21 Pg. 5043-56 (Nov 2010) ISSN: 1098-5549 [Electronic] United States
• PMID: 20733003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA Primers
• Dietary Fats
• Mark2 protein, mouse
• Mark3 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Adiposity (genetics, physiology)
• Alleles
• Animals
• Base Sequence
• Cell Cycle Proteins (genetics, physiology)
• Crosses, Genetic
• DNA Primers (genetics)
• Dietary Fats (administration & dosage)
• Embryonic Development (genetics, physiology)
• Energy Metabolism (genetics, physiology)
• Fatty Liver (enzymology, genetics, prevention & control)
• Female
• Gluconeogenesis (genetics, physiology)
• Insulin Resistance (genetics, physiology)
• Male
• Mice
• Mice, Knockout
• Obesity (enzymology, genetics, prevention & control)
• Phenotype
• Pregnancy
• Protein Serine-Threonine Kinases (deficiency, genetics, physiology)
• Starvation (enzymology, genetics, physiopathology)