Sex‐differential Expression of Metabolism‐related Genes in Response to a High‐fat Diet

Abstract

objective: The aim of this work was to determine the sex-associated differences in the expression of genes related to lipid metabolism and fuel partitioning in response to a high-fat (HF) diet in rats, and whether this is linked to the higher tendency of males to suffer from metabolic disorders. Methods and Procedures: Male and female Wistar rats were fed for 6 months on a normal-fat (NF) or an HF diet. Body weight, fat depot weight, lipid concentration in liver, blood metabolites, and the expression of genes involved in fuel metabolism and partitioning in the liver, white adipose tissue (WAT), and skeletal muscle were measured. Results: Female rats fed on an HF diet gained more weight and had a greater increase in the adiposity index than male rats, while the circulating insulin levels remained unaltered; these animals also showed an increased expression of genes related to the energy influx in WAT and with fat utilization in skeletal muscle. Male but not female rats showed increased hepatic peroxisome proliferator-activated receptor-α (PPAR-α) and CPT1L mRNA expression, suggesting enhanced lipid handling and oxidation by this organ, and have a higher triacylglycerol content in liver. Male rats under the HF diet also displayed higher blood insulin levels. Discussion: These results show sex-dependent differences in lipid handling and partitioning between tissues in response to an HF diet, with females showing a higher capacity for storing fat in adipose tissue and for oxidizing fatty acids in muscle. These adaptations can help to explain the lower tendency of females to suffer from obesity-linked disorders under the conditions of an HF diet.

Effect of high-fat diet feeding on leptin receptor expression in white adipose tissue in rats: depot- and sex-related differential response

“…Thus, although these results are only based on mRNA levels, the decrease in OB-Rb levels occurring in the internal depots studied, retroperitoneal and mesenteric, in male rats may contribute to increased peripheral leptin resistance in these internal depots and hence accelerate the metabolic impact of HF-diet feeding. Unlike male rats, the results of OB-Rb mRNA expression levels in these internal depots in female rats did not evidence increased leptin resistance under HF-diet feeding, in accordance with our previously published results [16].…”

“…The relative weights of all the depots studied were lower in female than in male rats. HF-diet feeding resulted in a significant increase in the size of fat stores, the retroperitoneal depot being the one with the highest increase in both male and female rats, as previously described [16]. Figure 2 shows OB-Rb, PPARa and CPT1 mRNA levels in the three different depots studied and the effects of diet and gender.…”

“…OB-Rb mRNA levels decreased in the retroperitoneal depot in both male and female rats; in the mesenteric depot, they decreased in males and increased in female rats; whereas the levels remained unchanged in the inguinal depot in both sexes. Depot-related differential responses to HF-diet feeding on the expression of metabolic-related genes have been previously described [16]. These differences are of interest considering the known relationship between fat-depot localization and function [26].…”

“…In addition to these factors, a sex differential regulation of the leptin receptor in WAT could be expected, as sex steroid hormones are closely involved in the metabolism, accumulation and distribution of adipose tissues [11], and a sex-dependent regulation of the expression of metabolic and fat partitioning-related genes has been previously described by our group [16].…”

“…Adipocyteselective reduction of the OB-Rb has been associated with obesity and type 2 diabetes [7]. We have previously described that male rats fed with an HF-diet have increased serum insulin levels and obesity-linked disorders, such as fat accumulation in the liver, while female rats did not present, at least to this extent, these metabolic complications [16]. OB-Rb abundance in the different depots may be determinant for an adequate response to an HF-diet.…”