The central and peropheral igf systems in the metabolic response to dietary change

Resumen

The insulin-like growth factor (IGF) system actively participates in the regulation of linear bone growth in the organism. However, this system is multi-functional, exerting important functions at both the peripheral and central levels including regulation of glycemia, participation in anabolic processes such as protein synthesis and lipid metabolism, promotion of cell proliferation and inhibition of apoptosis, among others. In addition, the two ligands of this system, IGF1 and IGF2, are also involved in processes of neuroprotection. However, there is limited information concerning the holistic regulation of this system in response to dietary challenges, including the implications of the IGF system in metabolic control at the hypothalamic level. The aims of this thesis were to determine how dietary challenges, particularly high-fat diet (HFD) consumption, affect the central and circulating IGF systems, and to explore the potential sex differences in this response. For this purpose, we exposed rodents to a HFD or low fat diet (LFD), as this diet has been widely used as the control diet for diet-induced obesity studies, compared to a chow diet during different periods of time to evaluate how the specific diet and/or changes in body weight modify the peripheral and central IGF systems. Moreover, the ability of this system and other metabolic parameters to recuperate upon weight loss was accessed. As the HFD employed was rich in palmitic acid (PA), a saturated fatty acid shown to be involved in many of the detrimental effects of poor dietary habits, we analyzed how PA might affect the hypothalamic IGF system. Astrocytes produce IGF1 and are involved in processes of neuroprotection; thus, the response of astrocytes to PA and the potential protection conferred by the IGF system in response to PA was explored in vitro by employing primary hypothalamic astrocyte cultures from male and female rat pups. The results of these studies indicate that whereas short-term HFD consumption has limited effects on the IGF system, long-term intake affects it both centrally and peripherally. Indeed, although most of the changes in the IGF system appear to be dependent on the overall nutritional-status, this system is also affected by the type of diet consumed, even before changes in body weight are observed, with males and females responding differently. Long-term HFD intake impairs glucose metabolism in males and alters the circulating IGF system, with the levels of most of its factors being restored after normalization of body weight. Female mice were initially more protected against the effects of HFD intake, as weight gain and modifications in glucose metabolism were delayed when compared to males. In addition, IGF2 and IGFBP2 levels correlated positively in the hypothalamus, suggesting a potential implication of both factors in the metabolic regulation. Although expression of the IGF system in hypothalamic astrocytes was dramatically affected by exposure to PA, IGF1 treatment was insufficient to counteract the toxic effects of this fatty acid. In astrocytes, changes in the levels of pregnancy-associated plasma protein-A (PAPP-A) and stanniocalcin-2 (STC-2) in response to PA could determine both IGF availability and cellular protection against this insult. Thus, these alterations of the IGF system in astrocytes after PA treatment may underlie, at least partially, the harmful effects of PA. Thus, the central and the peripheral IGF system are altered by dietary changes in a time and sex-dependent manner, with these alterations potentially affecting metabolism. In addition, the alterations in the IGF system in hypothalamic astrocytes caused by increased levels of PA have potential consequences not only in the metabolic response, but also affecting fundamental events such as cell survival