Anorexic effects of intra-VTA leptin are similar in low-fat and high-fat-fed rats but attenuated in a subgroup of high-fat-fed obese rats

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Abstract

Leptin is an adiposity hormone that plays an important role in regulating food intake and energy homeostasis. This study investigated the effects of a high-fat (HF) and a low-fat, high-carbohydrate/sugar (LF) diet on leptin sensitivity in the ventral tegmental area (VTA) in rats. The animals were exposed to a HF or LF diet for 16 weeks. Then the effects of intra-VTA leptin (150 and 500 ng/side, unilateral dose) on food intake and body weights were investigated while the animals were maintained on the HF or LF diet. Long-term exposure to the HF or LF diet led to similar body weight gain in these groups. The HF-fed animals consumed a smaller amount of food by weight than the LF-fed animals but both groups consumed the same amount of calories. The bilateral administration of leptin into the VTA decreased food intake (72 h) and body weights (48 h) to a similar degree in the HF and LF-fed animals. When the HF-fed animals were ranked by body weight gain it was shown that the diet-induced obese rats (HF-fed DIO, upper quartile for weight gain) were less sensitive to the effects of leptin on food intake and body weights than the diet-resistant rats (HF-fed DR, lower quartile for weight gain). A control experiment with fluorescent Cy3-labeled leptin showed that leptin did not spread beyond the borders of the VTA. This study indicates that leptin sensitivity in the VTA is the same in animals that are exposed to a HF or LF diet. However, HF-fed DIO rats are less sensitive to the effects of leptin in the VTA than HF-fed DR rats. Leptin resistance in the VTA might contribute to overeating and weight gain when exposed to a HF diet.

Highlights

► Decreased leptin sensitivity in the VTA of high-fat-fed obese rats. ► Long-term exposure to a high-fat diet does not affect leptin sensitivity in the VTA. ► Rats decrease food intake to compensate for an increased energy density of the diet.

Introduction

Since the 1970s, there has been a gradual increase in the prevalence of overweight and obesity (Flegal et al., 1998, Popkin and Doak, 1998). It has been suggested that this is due to an increased availability of food, an increase in the consumption of refined carbohydrates and fats, and an increasingly sedentary lifestyle (Swinburn et al., 2011). Animal models have been developed to investigate the neuronal mechanisms that cause overeating and obesity in humans. Several studies have shown that high-fat (HF) diets lead to increased weight gain in rats and mice (El Haschimi et al., 2000, Woods et al., 2003). The increased weight gain is accompanied by an increase in fat mass, an increase in plasma insulin and leptin levels, and insulin and leptin resistance (El Haschimi et al., 2000, Woods et al., 2003). Not all rats that are fed a HF diet gain more weight than control animals (Omagari et al., 2008). HF-fed animals that gain more weight than animals that are fed standard laboratory chow are often referred to as diet-induced obese (DIO) or obesity prone and the HF-fed animals that do not gain an excessive amount of weight are referred to as diet-resistant (DR) or obesity resistant (Farley et al., 2003, Levin et al., 1997, Levin et al., 1989, Otukonyong et al., 2005).

A wide variety of neuropeptides and hormones have been implicated in the regulation of food intake (Coll et al., 2007). Leptin is one of the hormones that fulfills the criteria for adiposity signal (Schwartz et al., 2000). Leptin is considered an adiposity signal because plasma levels of leptin are proportional to body fat content and leptin enters the brain in proportion to plasma levels (Schwartz et al., 1996). Second, leptin receptors are expressed on neurons that regulate food intake (Baskin et al., 1999). Third, the administration of leptin into the lateral ventricles and specific brain sites such as the arcuate hypothalamic nucleus (Arc) and the ventral tegmental area (VTA) reduces food intake whereas a deficiency in leptin leads to an increase in food intake (Bruijnzeel et al., 2011, Hommel et al., 2006, Satoh et al., 1997, Seeley et al., 1996, Zhang et al., 1994).

Leptin mediates some of its effects on metabolism and food intake via the phosphorylation of the transducer and activator of transcription 3 (STAT3) (Gao et al., 2004). Recent studies have used STAT3 phosphorylation as a marker to study leptin resistance (Matheny et al., 2011, Patterson et al., 2009). The administration of leptin into the third ventricle has been shown to induce STAT3 phosphorylation in the VTA and Arc and this effect is diminished in animals that have been exposed to a HF diet (Matheny et al., 2011). At this point, it is not known if long-term exposure to a HF diet would also affect the intra-VTA leptin-induced decrease in food intake and body weights. In addition, it is not known if the administration of leptin into the VTA affects food intake and body weights differently in HF-fed DIO and HF-fed DR rats. Therefore, the first aim of the present study was to investigate if long-term, 16 weeks, exposure to a HF diet affects the intra-VTA leptin-induced decrease in food intake and body weights in rats. The second aim was to investigate if leptin affects food intake and body weights differently in HF-fed DIO and DR rats.

Section snippets

Subjects

Male Sprague–Dawley rats (n = 42; Harlan labs, Prattville, AL) weighing 135–150 g (5–6 weeks of age) at the beginning of the experiment were used. Animals were single housed in a temperature- and humidity-controlled vivarium and maintained on a 12 h light–dark cycle (lights off at 9 AM). Food and water were available ad libitum in the home cages during all stages of the experiment. All subjects were treated in accordance with the National Institutes of Health guidelines regarding the principles of

Results

There were no differences in body weights between the HF and LF-fed rats prior to switching to the HF or LF diets (Fig. 2A; Diet: F1,40 = 0.42, n.s.). The rats were exposed to the HF or LF diet for 16 weeks and during this period the animals in the HF and LF-fed groups gained the same amount of weight (Fig. 2A; Diet: F1,39 = 0.84, n.s.; Time: F11,429 = 24.43, P < 0.0001). The animals that were exposed to the HF diet consumed a smaller amount of food by weight than the animals that were exposed to the LF

Discussion

The present study showed that the administration of leptin into the VTA led to a similar decrease in food intake and body weights in HF-fed and LF-fed rats. An additional analysis showed that HF-fed DIO rats were less sensitive to the effects of leptin on food intake and body weights than HF-fed DR rats. This study suggests that leptin signaling in the VTA plays a role in the regulation of food intake and heightened leptin sensitivity in the VTA may protect against overeating and obesity.

In the

Acknowledgments

This research was funded by a National Institute on Drug Abuse grant DA020502 to Adrie Bruijnzeel.

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