Short-term leptin treatment increases fatty acids uptake and oxidation in muscle of high fat–fed rats☆
Introduction
The impairment of insulin-stimulated glucose uptake by high concentrations of circulating fatty acids (FA) induced by either intralipid infusion or adherence to a high-fat (HF) diet has been well documented [1], [2], [3], [4] and suggests that alterations in muscle FA metabolism may be involved in the development of insulin resistance. In line with this notion, muscle triglyceride (mTG) accumulation has been shown to negatively correlate with whole-body insulin-stimulated glucose uptake [5], [6]. Although mTG accumulation can occur because of alterations in FA uptake, FA oxidation and/or FA esterification into mTG under both basal and insulin-stimulated conditions, it is not clear which of these metabolic pathways are the most affected by a HF diet. We have demonstrated that 3 weeks of HF feeding (65% fat-derived energy) is accompanied by mTG accumulation, a decrease in glucose uptake, and an increase in FA oxidation in muscle perfused under insulin-stimulated conditions [7]. These results suggest that resistance to the actions of insulin is present in muscle of HF-fed rats not only as it pertains to glucose uptake but also to the antioxidative actions of insulin on FA disposal [7]. However, it is not known whether the increase in mTG associated with HF feeding of a longer duration would be associated with further alterations in muscle FA kinetics under insulin-stimulated conditions.
Although it is generally accepted that alterations in FA metabolism are involved in the development of muscle insulin resistance, clinical strategies aimed at preventing the development of these metabolic pathologies are still highly debated [8]. Treatment with leptin is one of the pharmacologic interventions that have been studied because of its ability to improve insulin sensitivity in muscle [9]. Leptin is the 16-kd product of the ob gene, which is secreted by adipocytes in proportion to the amount of stored lipid [10]. Early studies have shown that leptin decreases food intake and regulates energy expenditure possibly via inhibition of neuropeptide Y release from the hypothalamus [11]. However, in line with the observation that isoforms of the leptin receptor are expressed in peripheral tissues such as skeletal muscle [12], [13], more recent studies have shown that acute leptin administration alters both glucose and FA metabolism in skeletal muscle [14], [15]. In isolated mouse soleus muscle incubated without insulin, short-term leptin treatment has been shown to increase FA oxidation and to decrease mTG synthesis [14]. In animals that have been administered a normal diet, short-term (<2 weeks) leptin treatment has also been reported to increase mTG hydrolysis in isolated rat soleus muscle incubated without insulin [16], to decrease FA transport into muscle giant sarcolemmal vesicles [17], and to reduce plasma membrane expression of FAT/CD36 and FABPPM in muscle [17]. These leptin-induced alterations in FA metabolism were associated with a decrease in mTG, suggesting that the insulin sensitizing effects of short-term leptin treatment on muscle glucose uptake [18] may be due in part to alterations in FA metabolism. In HF-fed rats, only the effects of short-term leptin treatment on basal FA metabolism have been studied in skeletal muscle and it was shown that the leptin-induced increase in FA oxidation and decrease in mTG synthesis observed in rats fed with normal rat chow was eliminated in rats fed a HF diet for 4 weeks [19]. These results suggested that with the accumulation of mTG induced by a HF diet, skeletal muscle develops not only insulin resistance but also leptin resistance [19]. Therefore, it is not known whether the insulin sensitizing effects of short-term leptin treatment on muscle glucose uptake observed in HF-fed rats would be associated with alterations in FA metabolism as shown in rats fed with normal rat chow [16], [17].
Thus, the aims of this investigation were (1) to evaluate the effects of long-term (3 months) HF feeding on FA metabolism in muscle perfused under insulin-stimulated conditions and (2) to investigate the effects of short-term (10 days) leptin treatment on insulin sensitivity as it pertains to FA uptake, oxidation, and mTG synthesis in animals that have been administered an HF diet for 3 months.
Section snippets
Animals
Seven-week-old male Wistar rats were randomly assigned to 1 of 4 groups whose initial body mass was not different (P > .05) between groups. One group was fed a control (CON) diet and 3 groups were fed a HF diet. The CON group (n = 8) was fed a low fat rat chow containing 4% fat, 24% protein, and 72% carbohydrate (Harlan Teklad, Madison, Wis), and given saline injections twice per day at 8:00 am and 5:00 pm. The HF group (HF; n = 8) was fed a diet consisting of 65% fat, 22% protein, and 13%
Animal and perfusion characteristics
HF animals recorded a greater energy expenditure than all other groups, whereas energy expenditure was lower in the HF-LEP and HF-P groups relative to HF and CON animals (Table 1). After the 3 months of dietary manipulation, body mass was not significantly different between groups (P > .05) and averaged 474.9 ± 11.6 g in the CON group (n = 8) and 479.2 ± 14.2 g in the HF-fed groups (n = 24) (Table 1). Although the 10-day leptin treatment and pair-feeding regimen decreased body mass by 1.6% to
Discussion
Our results show that muscle FA metabolism under insulin-stimulated conditions is altered by 3 months of HF feeding and is accompanied by resistance to the antioxidative actions of insulin but not to the lipogenic actions of insulin as shown by the high rate of FA oxidation and mTG synthesis in HF-fed rats. Our results also show that short-term leptin treatment in HF-fed rats increases FA uptake and oxidation independently of the leptin-induced food restriction and is accompanied by a reduction
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The present study was supported by the National Institutes of Health grants GM-48680 (BBY), DK-57625 (BBY), and AR-45168 (LPT), and by a grant from Amgen Inc (BBY).