Resistance to obesity in Lou/C rats prevents ageing-associated metabolic alterations

Abstract

Aims/Hypothesis. Ageing is associated with metabolic alterations characterised by changes in energy expenditure, obesity, leptin and insulin resistance. The Lou/C rat, an inbred strain of Wistar origin, is presented as both an obesity-resistant rat and a model of healthy ageing. Methods. To characterise the mechanisms underlying obesity resistance in Lou/C rat, we measured food intake and energy expenditure by indirect calorimetry at 1, 6, 12, 18, and 24 months of age. Moreover, plasma insulin and leptin concentrations were assessed by radioimmunoassay in Lou/C and Wistar rats throughout their life span. Results. Compared to Wistar rats, Lou/C rats presented a higher food intake only at 24 months of age and they had a higher energy expenditure at 6 and 12 months of age (+21% and +14%, respectively). Plasma insulin concentration increased markedly in 18-and 24-month-old Wistar rats, but remained stable during ageing in Lou/C rats. From the age of 6 months, the plasma leptin concentrations in Wistar rats were higher than in Lou/C rats of the same age (four-, seven-, five-and threefold higher at 6, 12, 18, 24 months of age, respectively). Conclusion/interpretation. Compared to Wistar rats, Lou/C rats did not develop insulin resistance as confirmed by a higher glucose infusion rate during the hyperinsulinaemic-euglycaemic clamp. These data provide evidence that insulin resistance is associated with the excess of adipose tissue in Wistar rats. Not only Lou/C rats present a higher median life span than Wistar rats (+20%), but they also show a healthy ageing process considering fat accretion and insulin resistance. [Diabetologia (2003[Diabetologia ( ) 46:1489[Diabetologia ( -1496 Keywords Insulin resistance, energy expenditure, leptin, ageing, Lou/C rat, food intake. lin. Insulin is considered as an adiposity signal. Its plasma concentration is associated with the amount of fat stores [1,2] and insulin receptors are expressed in the brain, especially in the paraventricular nuclei involved in the control of energy intake [3,4]. Insulin resistance is associated with fat accretion [5] and/or with the effect of ageing on the insulin receptor [6]. Leptin, which is secreted by adipocytes, provides feedback information on the lipid stores towards the hypothalamus. Leptin contributes to the regulation of both food intake and energy expenditure [7,8]. The plasma leptin concentration is directly related to body fat mass [9,10] but during ageing, increased concentrations of plasma leptin appears dissociated from fat stores [11]. However, it is extremely difficult to differAgeing is associated with metabolic disorder characterised notably by changes in energy expenditure, fat distribution leading to increased adiposity and insulin resistance.Several hormones can affect both energy expenditure and fat mass, amongst which are leptin and insu-

Lack of starvation-induced activation of AMP-activated protein kinase in the hypothalamus of the Lou/C rats resistant to obesity

“…5,6 Thus, we confirmed here that starvation induced a threefold decrease in circulating leptin (Table 2), which correlated with an activation of AMPK in the hypothalamus of Wistar rats. However, while the leptin level was significantly reduced in fed Lou/C rats, as previously reported, 19,20,26 the starvation-induced decrease in leptin concentration evidenced in Wistar was not present in Lou/C rats. The Janus kinase (JAK)-STAT pathway is believed to mediate leptin signaling in the hypothalamus mainly via an increase in STAT3 phosphorylation.…”

“…The aim of our work was to investigate whether perturbation of hypothalamic AMPK regulation could be detected in the spontaneously hypophagic Lou/C rats, a strain derived from Wistar rat 17 and resistant to age-related obesity. [18][19][20] Methods Animals Three-month-old age-paired male Lou/C and Wistar rats were kept in a controlled temperature (20-23 1C) and light (12 h/12 h cycle) environment with ad libitum access to food and water. Starvation was induced by food withdrawal 24 h before killing (at 0900 hours).…”

Established diet-induced obesity in female rats leads to offspring hyperphagia, adiposity and insulin resistance

“…Euglycaemic-hyperinsulinaemic clamp (offspring) Euglycaemic-hyperinsulinaemic clamps were carried out according to Perrin et al [22], but in awake and semi-restrained animals. Females (one per litter) were studied at 8 to 9 months and males (one per litter) at 10 to 11 months.…”

Liver mitochondrial properties from the obesity-resistant Lou/C rat

“…[2][3][4] Indeed, Wistar or Fisher 344 strains develop spontaneous obesity with ageing, 5,6 whereas Lou/C rats exhibit a stable adiposity throughout life associated with an inborn low caloric intake (LCI). 1,4,7,8 Although the mechanisms responsible for low energy intake and resistance to obesity of the Lou/C rats are probably multifactorial, it must be kept in mind that LCI while avoiding malnutrition is reputed for reducing the incidence and retarding the onset of numerous age-related biological processes.…”

“…[2][3][4] Indeed, Wistar or Fisher 344 strains develop spontaneous obesity with ageing, 5,6 whereas Lou/C rats exhibit a stable adiposity throughout life associated with an inborn low caloric intake (LCI). 1,4,7,8 Although the mechanisms responsible for low energy intake and resistance to obesity of the Lou/C rats are probably multifactorial, it must be kept in mind that LCI while avoiding malnutrition is reputed for reducing the incidence and retarding the onset of numerous age-related biological processes. 7,[9][10][11][12] The mechanisms underlying the robust and widespread protective effects of LCI remain to be clearly identified, but a leading hypothesis suggests that the effects of LCI may be due to a reduced generation of reactive oxygen species (ROS) by mitochondria.…”