Partial inactivation of Ankrd26 causes diabetes with enhanced insulin responsiveness of adipose tissue in mice

• Published in: Diabetologia Vol. 54; no. 11; pp. 2911 - 2922
• Main Authors: Raciti, G. A., Bera, T. K., Gavrilova, O., Pastan, I.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-11-2011; Springer; Springer Nature B.V
• Subjects: Adipose Tissue, White - metabolism; Animals; Appetite Regulation; Biological and medical sciences; Body fat; Caloric Restriction; Cancer; Diabetes; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - prevention & control; Diabetes. Impaired glucose tolerance; Diet; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Food; Glucagon; Glucose; Glucose Intolerance - etiology; Glucose Intolerance - metabolism; Glucose Intolerance - prevention & control; Human Physiology; Hypotheses; Insulin - metabolism; Insulin Resistance; Internal Medicine; Kidney diseases; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutant Proteins - physiology; Obesity; Obesity - diet therapy; Obesity - metabolism; Obesity - physiopathology; Obesity - prevention & control; Organ Specificity; Phosphorylation; Protein Processing, Post-Translational; Proteins; Random Allocation; Receptor, Insulin - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - physiology; Young adults; United States > US; Energy intake restriction; Obesity; Diabetes; WAT; Insulin sensitivity; Endocrinopathy; Pancreatic hormone; Adipose tissue; Diabetes mellitus; Rodentia; Nutrition disorder; Inactivation; Insulin; Vertebrata; Sensitivity; Mammalia; Mouse; Animal; Ankrd26; Nutritional status
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2263-9

Aims/hypothesis
ANKRD26
is a newly described gene located at 10p12 in humans, a locus that has been identified with some forms of hereditary obesity. Previous studies have shown that partial inactivation of
Ankrd26
in mice causes hyperphagia, obesity and gigantism. Hypothesising that
Ankrd26
mutant (MT) mice could develop diabetes, we sought to establish whether the observed phenotype could be (1) solely related to the development of obesity or (2) caused by a direct action of ankyrin repeat domain 26 (ANKRD26) in peripheral tissues.
Methods
To test the hypothesis, we did a full metabolic characterisation of
Ankrd26
MT mice that had free access to chow or were placed under two different energy-restricted dietary regimens.
Results
Highly obese
Ankrd26
MT mice developed an unusual form of diabetes in which white adipose tissue is insulin-sensitive, while other tissues are insulin-resistant. When obese MT mice were placed on a food-restricted diet, their weight and glucose homeostasis returned to normal. In addition, when young MT mice were placed on a pair-feeding diet with normal mice, they maintained normal body weight, but showed better glucose tolerance than normal mice, an increased responsiveness of white adipose tissue to insulin and enhanced phosphorylation of the insulin receptor.
Conclusions/interpretation
These findings show that the ANKRD26 protein has at least two functions in mice. One is to control the response of white adipose tissue to insulin; the other is to control appetite, which when
Ankrd26
is mutated, leads to hyperphagia and diabetes in an obesity-dependent manner.