Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice

Abstract

Ataxin-2 is a cytoplasmic protein, product of the SCA2 gene. Expansion of the normal polyglutamine tract in the protein leads to the neurodegenerative disorder Spino-Cerebellar Ataxia type 2 (SCA2). Although ataxin-2 has been related to polyribosomes, endocytosis and actin-cytoskeleton organization, its biological function remains unknown. In the present study, an ataxin-2 deficient mouse (Sca2(-/-)) was generated to investigate the functional role of this protein. Homozygous mice exhibited reduced fertility and locomotor hyperactivity. In analyses up to the age of 6 months, the absence of ataxin-2 led to abdominal obesity and hepatosteatosis. This was associated with reduced insulin receptor expression in liver and cerebellum, although the mRNA levels were increased indicating a post-transcriptional effect of ataxin-2 on the insulin receptor status. As in insulin resistance syndromes, insulin levels were increased in pancreas and blood serum. In the cerebellum, increased levels of gangliosides and sulfatides, as well as decreased cholesterol dynamics, may be relevant for cellular membrane functions, and alterations in the sphingomyelin cycle may affect second messengers. Thus, the data suggest altered signaling in ataxin-2 deficient organisms.

Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

“…Thus, our proteomic findings correspond well to the previous documentation of chronic accumulation of lipid droplets and glycogen in the liver of Atxn2-KO mice (30). It is known that elevated blood plasma levels of BCAAs serve as markers of obesity, insulin resistance and diabetes mellitus (55), so they are key indicators of metabolic excess.…”

“…Atxn2-KO was verified by genotyping of tail biopsies at the DNA level as previously described (30) and verified in the tissues under study by real-time qPCR at the mRNA level. Additionally, we looked at the proteome level for the evidence of ATXN2 presence in all samples, and observed six different ATXN2 specific peptides exclusively in wild-type (WT) samples, never in KO samples (data not shown).…”

“…All analyses were performed on male mice with a mixed C57BL/6 _ 129/Ola background. Genotyping was performed with tail biopsies by PCR with three sets of primers as previously described (30).…”

“…In mice, two independent Atxn2-knock-out (KO) lines confirmed phenotypes of obesity (30,31), with excessive liver fat and glycogen deposits, insulin resistance, and dyslipidemia also being noted by the age of 6 months. Thus, even in the absence of high-fat-diet and within the short lifespan of rodents, the monogenic deficiency of Ataxin-2 is sufficient to trigger important features of the human metabolic syndrome.…”

Mechanism of Lipid Induced Insulin Resistance: An Overview

“…Reduced IR expression has been observed in mice and also in human diabetic patients [41,42] and PKCε has been implicated in IR damage. IR expression is inversely correlated to PKCε in diabetic obese rats [43] and lipid mediated hepatic insulin resistance has been shown to be prevented by knocking down of PKCε [44].…”