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Y Wang, Research, The Jackson Laboratory, Bar Harbor, United States
Y Zheng, Research, The Jackson Laboratory, Bar Harbor, United States
P Nishina, Research, The Jackson Laboratory, Bar Harbor, United States
J Naggert, Diabetes research, The Jackson Laboratory, Bar Harbor, 04609, United States

Correspondence: Jürgen Naggert, Email: jkn{at}jax.org

Metabolic Syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy.

A backcross was used to genetically map the Nmf15 locus. Mice were examined in the CLAMSTM animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Leptin-induced STAT3 phosphorylation in the hypothalamus was examined. Cardiac function was assessed by Echo- and Electro Cardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity.

The Nmf15 locus mapped to distal mouse chromosome 5 with a LOD score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly elevated in pre-obese Nmf15 mice at 8 weeks of age and an attenuated STAT3 phosphorylation in the hypothalamus suggests a primary leptin resistance. Adipose tissue from Nmf15 mice showed a remarkable degree of inflammation and macrophage infiltration as indicated by expression of the F4/80 marker and increased phosphorylation of JNK1/2. Lipidosis was observed in tubular epithelial cells and glomeruli of the kidney. Nmf15 mice demonstrate both histological and pathophysiological evidence of cardiomyopathy.

The Nmf15 mouse model provides a new entry point into pathways mediating leptin resistance and obesity. It is one of few models that combine many aspects of metabolic syndrome and can be useful for testing new therapeutic approaches for combating obesity complications, particularly cardiomyopathy.