Jacobs 2014

Loss of Ciliary Gene, Thm1, Causes Hyperphagia-Induced Obesity, Fatty Liver Disease, Pre-Diabetes, and Hypertension

Damon T Jacobs1, Michael P Schonfeld1, Luciane M Silva1, Anindita Chatterjee1, George C Talbott2, David R Beier2,3 and Pamela V Tran1

1Department of Anatomy and Cell Biology, Kidney Institute, University of Kansas Medical Center, Kansas City, KS 2Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 3Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA

Primary cilia are antenna-like structures present on most vertebrate cells that mediate signaling pathways. Cilia defects cause ciliopathies, which manifest common clinical features, such as obesity. Obesity is a worldwide epidemic that affects several physiological systems. Treatments for obesity-related conditions are costly, invasive and largely ineffective. The IFT complex A gene, Thm1, negatively regulates Hedgehog (Hh) signaling and is the most commonly mutated gene in ciliopathies. We examined a role for murine Thm1 in obesity using a Thm1 conditional knock-out (cko) allele together with a ubiquitous, tamoxifen-inducible Cre recombinase. While Thm1 deletion during late embryogenesis resulted in cystic kidney disease, Thm1 deletion during adulthood caused a two-fold weight gain relative to wild-type mice over a 13-week period. In adult Thm1 cko mice, adipose depots were significantly larger than in wild-type, and Thm1
cko livers had numerous lipid droplets, indicative of fatty liver disease. Thm1 cko serum glucose was elevated and mice were unable to efficiently clear a glucose challenge in glucose tolerance tests, suggesting a pre-diabetic/diabetic state. Additionally, serum leptin and insulin levels were elevated several fold. Thm1 cko mice also showed increased systolic and diastolic arterial blood pressures relative to control mice. Together, these observations indicate metabolic distress or ‘metabolic syndrome’. To determine if the 19% increase in food intake observed in Thm1 cko mice caused the obese phenotype, Thm1 cko mice were pair-fed for 13 weeks following Thm1 deletion. Indeed, body weights and fat depots of pair-fed Thm1 cko mice were similar to wild-type, indicating hyperphagia is a primary cause of obesity. In the arcuate nucleus of the hypothalamus, Thm1 cko primary cilia are stunted. We are examining signaling pathways that are differentially regulated in the Thm1 cko hypothalamus that may play a role in hyperphagia.