Heterozygosity for leptin receptor (fa) accelerates hepatic triglyceride accumulation without hyperphagia in Zucker rats

Summary

Leptin, ob gene product, and its receptors are involved in the regulation of peripheral lipid and glucose metabolism. The present study sought to clarify the functional role of peripheral leptin receptors in hepatic lipid metabolism through analysis of Zucker rats (fa/fa, +/fa), as complete or partial leptin receptor insufficiency models, respectively. In Zucker fa/fa rats, calorie intake, body weight, liver weight, hepatic triglyceride content and serum insulin, triglycerides, FFA, and leptin were elevated compared to lean littermates (+/+ rats). In contrast, Zucker +/fa rats showed no remarkable changes in calorie intake, body weight and serum FFA compared with +/+ rats. Nevertheless, hepatic triglyceride content, liver weight and other serum parameters such as insulin, triglyceride and leptin were higher than in +/+ rats. In the representation of fatty acids component in the liver, there were no changes in +/fa rats relative to +/+ rats. Thus, in Zucker +/fa rats, fatty liver may develop in the absence of hyperphagia, obesity or changes in hepatic fatty acid metabolism. These results indicate that partial insufficiency of leptin receptor rather than changes in serum insulin, triglyceride and leptin may contribute to the increase in hepatic triglyceride content observed in +/fa rats.

Introduction

Reflecting its wide range of physiological functions, receptors for leptin are distributed widely throughout the body. Notably, leptin receptors have been shown to be expressed at relatively high levels in the hypothalamus, the choroid plexus, the lung and the kidney, and at lower levels in the liver, adipose tissue, skeletal muscle and the pancreas [1]. The abundance of leptin receptors in the brain and the dramatic effects of centrally administered leptin on feeding behavior and body weight indicate that the hypothalamus is the major target of leptin [2], [3], [4]. On the other hand, in vivo and in vitro studies have demonstrated functional significance of peripheral adipocytokines action including leptin in the regulation of metabolic disorder [5], [6], [7]. Especially in the liver, leptin has been shown to inhibit intracellular lipid concentration by reducing synthesis of triglyceride and concomitantly increasing β-oxidation of fatty acids [7]. This indicates that leptin receptor insufficiency induced by genetic defect or acquired leptin resistance, even at the peripheral level, may induce abnormal peripheral lipid metabolism, such as hyperlipidemia and fatty liver, independent of a distortion of central leptin action, which would lead to hyperphagia.

Zucker fatty (fa/fa) rats, which are leptin receptor defective animals, are useful for analyzing various metabolic disorders induced by disruption of leptin signaling [8]. In fact, hypertriglyceridemia, hyperinsulinemia, hyperleptinemia and severe fatty liver have been observed in this obese animal. In Zucker fa/fa rats, however, it is difficult to distinguish the relative contributions of peripheral and central leptin signaling because disruption of hypothalamic leptin signaling induces hyperphagia, which in turn affects peripheral lipid metabolism. Furthermore, inactivation of efferent sympathetic outflow in Zucker fa/fa rats [9], which is normally activated by centrally mediated leptin action [9], [10], may also affect peripheral lipid metabolism as well as energy expenditure, as regulated by uncoupling proteins (UCP) [11], [12].

On the other hand, Zucker +/fa rats, lean heterozygotes with partial leptin receptor defects, are non-obese and non-hyperphagic, indicating partial leptin receptor insufficiency is not sufficient to cause the fa/fa phenotype. There have been very few studies that address whether this partial leptin signaling insufficiency affects other metabolic parameters. It has been reported that adult mice heterozygous for the ob or db allele display increased body fat compared with their lean +/+ littermates [13]. Thus, these previous findings indicate that even partial insufficiency of leptin signaling can affect peripheral lipid metabolism. Based on this background, we used Zucker +/fa rats to clarify whether or not hepatic lipid metabolism is affected in these animals, and whether this was due to either disruption of peripheral leptin signaling, hyperphagia, or a metabolic disorder.