# ZSF1 lean rats – How healthy are they?

## TL;DR

ZSF1 lean rats, used as controls in obesity studies, show subtle heart and vascular changes compared to healthy rats, suggesting they may not be fully healthy.

## Contribution

This study reveals physiological differences in ZSF1 lean rats that question their use as healthy controls in cardiometabolic research.

## Key findings

- ZSF1 lean rats have increased heart and skeletal muscle mass but lower body weight compared to Wistar rats.
- ZSF1 lean rats show elevated left ventricular filling pressure and myocardial stiffness despite preserved cardiac function.
- Vascular smooth muscle responsiveness is reduced in ZSF1 lean rats, with increased passive vascular stiffness.

## Abstract

ZSF1 lean rats are widely used as controls in cardiometabolic studies involving ZSF1 obese rats, which develop a cardiometabolic syndrome and diastolic dysfunction at a young age due to a double leptin receptor mutation (Leprcp and Leprfa). Although, lean littermates show no overt signs of cardiometabolic disease or diastolic impact, they belong to one of three genotypic variants, two of which carry one of the mutant Lepr alleles and, thus, doubt has been raised about their suitability as healthy controls. We compared 32‐week‐old female ZSF1 lean and Wistar rats regarding physiological, myocardial, vascular, skeletal muscle, and mitochondrial characteristics. Lean rats showed lower body weight but increased heart, kidney, and skeletal muscle mass. Despite thicker ventricular walls, systolic and diastolic function were preserved. Hemodynamically measured contractility was higher as underpinned by a higher mitochondrial respiratory capacity of LV fibers. However, left ventricular filling pressure was elevated, accompanied by increased ventricular stiffness. Endothelial function was preserved, but smooth muscle responsiveness was reduced, indicated by impaired SNP‐induced relaxation. Passive vascular stiffness mediated by collagenous fibers was significantly higher in lean rats. Skeletal muscle function was mostly preserved, though maximal specific force of the EDL was reduced. Taken together, ZSF1 lean rats are physiologically different from Wistar rats as they display enlarged myocardial dimensions accompanied by increased blood pressure and an incipient diastolic and vascular stiffness. Therefore, our data indicate an early phase of passive compliance disorder in ZSF1 lean animals, which might become more pronounced at an advanced age.

This study aimed to examine the health status, specifically the physiology and myocardial, vascular, and skeletal muscle function of lean ZSF1 rats by comparing them to age‐ and sex‐matched Wistar rats. Compared to Wistar controls, ZSF1 lean rats exhibited lower body weight, but showed increased heart, and skeletal muscle mass. Cardiac systolic and diastolic function were preserved, though left ventricular filling pressure and myocardial stiffness were elevated. Hemodynamic measurements revealed enhanced left ventricular filling and mean arterial pressure. While endothelial function was unaltered, vascular smooth muscle responsiveness was reduced, as indicated by impaired SNP‐induced relaxation and increased passive vascular stiffness. Although maximal specific force of the EDL muscle was reduced, skeletal muscle function was largely preserved.