Leptin resistance: a prediposing factor for diet-induced obesity

Abstract

Obesity is a resilient and complex chronic disease. One potential causative factor in the obesity syndrome is leptin resistance. Leptin behaves as a potent anorexic and energy-enhancing hormone in most young or lean animals, but its effects are diminished or lacking in the obese state associated with a normal genetic background. Emerging evidence suggests that leptin resistance predisposes the animal to exacerbated diet-induced obesity (DIO). Elevation of central leptin in young, lean rats induces a leptin resistance that precludes obesity on a chow diet but accelerates high-fat (HF)-induced obesity. Similarly, chronic dietary fructose consumption evokes a leptin resistance that causes obesity only upon HF exposure. Inherent central leptin insensitivity also contributes to dietary weight gain in certain obesity-prone rats. Conversely, aged, leptin-resistant animals are obese with continuous chow feeding and demonstrate aggravated obesity when challenged with an HF diet. Additionally, a submaximal central blockade with a leptin antagonist leads to obesity on both chow and HF diets, as is the case in rodents with leptin receptor deficiency of genetic origin. Despite the differences in the incidence of obesity on a chow diet, all of these forms of leptin resistance predispose rodents to aggravated HF-mediated obesity. Moreover, once leptin resistance takes hold, it aggravates DIO, and the leptin resistance and obesity compound one another, promoting a vicious cycle of escalating weight gain.

Fig. 1.

A: body weight gain following a high-fat (HF) diet in rats pretreated for 94 days with control vector or rAAV-leptin compared with chow-fed rats pretreated with control vector. Values are means ± SE of 8 rats/group. In some cases, SE bars are less than the size of the data point (P < 0.001 for difference in body weight gain between all pairs by one-way ANOVA). (A is modified from Ref. 70). B: body weight gain following HF feeding in 3-mo-old and 30-mo-old rats. Data are means ± SE of 21 3-mo-old and 5 30-mo-old rats. Body weight gain in the 30-mo-old rats was greater than the 3-mo-old rats beginning at day 3 (P < 0.01, one-way ANOVA). (B is adapted from Ref. 26). C: body weight gain in rats pretreated with a fructose free or high fructose diet for 6 mo and then either maintained on the fructose-free control or high-fructose diets or switched to a 60% high-fat diet. Values are means ± SE of 5–6 animals/group (P < 0.01 for difference between high fructose/high fat and control/high fat weight gain beginning at day 1. (C is adapted from Ref. 62). D: body weight gain following administration of control vector or rAAV-leptin in DIO rats. The rAAV-leptin or control vectors were administered in rats raised on an HF diet for 5 mo and continued on the HF diet throughout the experiment. Values are means ± SE of 6 rats/group (P < 0.05 for difference in slopes beginning at day 20 after vector administration). (D is adapted from Ref. 61).

Fig. 2.

Daily caloric intake (A) and body weight gain (B) in HF-fed rats following a 7-day infusion of antagonist (25 μg/day) or vehicle and in chow-fed rats following vehicle infusion. The antagonist or vehicle infusion and HF feeding started at day 0. Values are means ± SE of 9 antagonist/HF, 8 control/HF, and 8 control/chow rats. Food intake data are expressed as caloric intake per day, based on 3.10 kcal/g of chow and 5.24 kcal/g of HF diet. Caloric intake and body weight significantly differed between antagonist/HF and control/HF beginning at day 1 (P < 0.01). (Figure 2 is adapted from Ref. 67).