Kv1.3 gene-targeted deletion reduces fat deposition and total body weight in melanocortin 4 receptor (MC4R)-null mice: A model of hypothalamic-driven late-onset obesity

• Published in: Appetite Vol. 49; no. 1; p. 336
• Main Authors: Tucker, K., Overton, J.M., Fadool, D.A.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.07.2007
• ISSN: 0195-6663; 1095-8304
• DOI: 10.1016/j.appet.2007.03.204

Mice with gene-targeted deletion of Kv1.3, a voltage-gated potassium channel of the Shaker family, are thin and do not gain weight when challenged with a moderately high-fat diet. Kv1.3 has been shown to modulate glucose uptake in white adipose tissue and be expressed by mitochondria. Kv1.3 is also expressed in brain regions important for feeding and metabolism such as the hypothalamus and olfactory bulb, where its activity is modulated by insulin. To address hypothalamic Kv1.3 contribution, we generated doubly homozygous MC4R/Kv1.3-null mice (mmkk) to ascertain if deletion of Kv1.3 channel protein could abrogate weight gain in a model of hypothalamic obesity. At 9 months, mmkk mice weighed 18% less than MC4R-null mice. This phenomenon began to emerge around postnatal day 60 (P60) at which point there is lower visceral and subcutaneous fat pad deposition in the mmkk mice with no change in nose to anus length. To characterize the onset of the reduced adiposity phenotype, locomotor activity, mass-specific metabolic rate ( V O2), and ingestive behaviors were monitored in P60–P75 mice. These experiments revealed no differences in ingestive behaviors but locomotor activity (66% in females, 50% in males) and V O2 (21% in females, 12% in males) were increased in mmkk mice above that of MC4R-null mice. These results indicate Kv1.3 deletion reduces fat deposition and total body weight in a model of hypothalamic-driven, late-onset obesity possibly through increased locomotor activity and V O2. This work was supported by: NIH DC 003387 and DC 00044, and FSU CRC Competitive Planning Grant.