Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain

Abstract

Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the JCR:LA-cp rat model was developed with an autosomal recessive corpulent (cp) trait resulting from a premature stop codon in the extracellular domain of the leptin receptor. Rats that are heterozygous for the cp trait are lean-prone, while those that are homozygous (cp/cp) spontaneously display the pathophysiology of obesity as well as a metabolic syndrome (MetS)-like phenotype. Over the years, there have been formidable scientific contributions that have originated from this rat model, much of which has been reviewed extensively up to 2008. The premise of these earlier studies focused on characterizing the pathophysiology of MetS-like phenotype that was spontaneously apparent in this model. The purpose of this review is to highlight areas of recent advancement made possible by this model including; emerging appreciation of the “thrifty gene” hypothesis in the context of obesity, the concept of how chronic inflammation may drive obesogenesis, the impact of acute forms of inflammation to the brain and periphery during chronic obesity, the role of dysfunctional insulin metabolism on lipid metabolism and vascular damage, and the mechanistic basis for altered vascular function as well as novel parallels between the human condition and the female JCR:LA-cp rat as a model for polycystic ovary disease (PCOS).

Editorial: Comorbidity and Autism Spectrum Disorder

“…This modifiable comorbidity, obesity, predisposes an individual to insulin resistance and type 2 diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, stroke, sleep apnea, gallbladder disease, hyperuricemia, gout, and osteoarthritis. Obesity has emerged as an epidemic among our ASD children who are plagued by both risk factors and an "obesogenic" environment (26). Prevention of excess weight gain is therefore a major target of personalized medicine meant to improve physical fitness in children with ASD (27)(28)(29).…”

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

“…Rats homozygous for the corpulent gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic, primarily due to hepatic hypersecretion of VLDL ( 150 ). The cp trait results from a premature stop codon in the extracellular domain of the leptin receptor and therefore these rats lack a functional leptin receptor ( 151 ). Among the different cp strains, the JCR:LA-cp rat strain displays hyperlipidemia associated with APOB48-containing lipoprotein particles, particularly in the early post-prandial phase ( 152 ), and vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions ( 54 ), consistent with a pro-atherogenic effect of VLDL or its lipolysis products.…”

The Influence of Diet and Sex on the Gut Microbiota of Lean and Obese JCR:LA-cp Rats

“…We, therefore, investigated the effect of a HFHS diet and flax feeding on a JCR:LA- cp rat model of genetic obesity in both male and female animals. The JCR:LA- cp rat has an autosomal recessive leptin receptor mutation [ 32 ]. Thus, JCR:LA- cp rats manifest an obese phenotype, along with metabolic syndrome-related abnormalities such as dyslipidemia, hepatic injury, atherosclerosis, and cardiac dysfunction [ 32 , 33 , 34 , 35 ].…”