Abstract
The AMP-activated protein kinase (AMPK) is involved in the control of food intake by the hypothalamus. The aim of this work was to investigate if modification of hypothalamic AMPK regulation could be related to the spontaneous food restriction of Lou/C rats, a strain resistant to obesity exhibiting a 40% reduction in caloric intake compared with their lean Wistar counterparts. Three-month-old male Lou/C rats were compared with age-matched male Wistar rats in both fed ad libitum and 24-h food deprivation state. We first confirmed that starvation activated both isoforms of AMPK catalytic alpha subunits and enhanced the phosphorylation state of its downstream targets acetyl-CoA carboxylase and elongation factor 2 in the hypothalamus of Wistar rats. These changes were not observed in the hypothalamus of Lou/C rats. Interestingly, the starvation-induced changes in hypothalamic mRNA levels of the main orexigenic and anorexigenic neuropeptides were also blunted in the Lou/C rats. Analysis of the concentrations of circulating substrates and hormones known to regulate hypothalamic AMPK indicated that the starvation-induced changes in ghrelin, adiponectin and leptin were not observed in Lou/C rats. Furthermore, an increased phosphorylation state of signal transducer and activator of transcription 3 (STAT3), which admittedly mediates leptin signaling, was evidenced in the hypothalamus of the starved Lou/C rats, as well as modifications of expression of the leptin-sensitive genes suppressor of cytokine signaling-3 and stearoyl-coenzyme A desaturase 1. In addition, despite reduced leptin level in fed Lou/C rats, the phosphorylation state of hypothalamic STAT3 remained similar to that found in fed Wistar rats, an adaptation that could be explained by the concomitant increase in ObRb leptin receptor mRNA expression. Activation of hypothalamic AMPK by starvation, which stimulates food intake through changes in (an)orexigenic neuropeptides in the normal rats, was not observed in the spontaneously hypophagic Lou/C rats.
Highlights
The hypothalamus plays a critical role in the regulation of energy homeostasis.[1,2,3] It regulates both feeding behavior and energy expenditure by integrating information from the periphery through nutrients and hormones such as glucose, Hypothalamic AMPK and food intake in Lou/C rats N Taleux et al[640] Several studies have recently shown that the AMP-activated protein kinase (AMPK) plays a central role in the regulation of food intake by the hypothalamus.[5,6,7,8] AMPK is a heterotrimeric serine/threonine protein kinase containing a catalytic (a) subunit and two regulatory (b and g) subunits
Spontaneous hypophagia of Lou/C rats The spontaneous hypophagia of Lou/C rats is already present at 3 weeks of age, immediately after weaning, reaches a plateau (BÀ40%) at 8 weeks of age and remains constant for the rest of their life
The lack of starvation-induced hypothalamic AMPK activation in Lou/C rats was associated with a 50% reduction in their cumulative food intake during the first 4 h following refeeding (Figure 1e)
Summary
The hypothalamus plays a critical role in the regulation of energy homeostasis.[1,2,3] It regulates both feeding behavior and energy expenditure by integrating information from the periphery through nutrients and hormones such as glucose, Hypothalamic AMPK and food intake in Lou/C rats N Taleux et al[640] Several studies have recently shown that the AMP-activated protein kinase (AMPK) plays a central role in the regulation of food intake by the hypothalamus.[5,6,7,8] AMPK is a heterotrimeric serine/threonine protein kinase containing a catalytic (a) subunit and two regulatory (b and g) subunits. Glucose, insulin and leptin, which are known to inhibit food intake, inactivate hypothalamic AMPK,[5] whereas ghrelin and adiponectin, which stimulate food intake, activate hypothalamic AMPK.[6,14] Antagonistic effects on food intake were observed after pharmacological modulation of intrahypothalamic ATP levels by intracerebroventricular injection of 2-deoxyglucose or the fatty acid synthase inhibitor C75.7 overexpression of a constitutively active form of AMPK5 or intracerebroventricular injection of AMPK activators in the hypothalamus[6] stimulated food intake and body weight gain, whereas expression of a dominantnegative mutant of AMPK5 had opposite effects This AMPKmediated control of food intake involves modifications of the hypothalamic mRNA content of the major orexigenic and anorexigenic neuropeptides[5,7,8] but the underlying mechanisms are still unknown.[11]
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