ESPE Abstracts (2019) 92 FC8.2

Analysis of Hypothalamic Metabolic Circuits after Normalization of Body Weight in Mice That Had Been Obese Due to High Fat Diet Intake

Santiago Guerra-Cantera 1,2,3, Laura Frago1,2,3, Purificación Ros2,4, Sandra Canelles1,3, Francisca Díaz1,3, Alejandra Freire-Regatillo 1,2,3, Marta Marta Torrecilla-Parra 1,2, Jesús Argente1,2,3,5, Julie A. Chowen1,3,5


1Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain. 2Department of Pediatrics, Universidad Autónoma of Madrid, Madrid, Spain. 3Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. 4Department of Pediatrics, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain. 5IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain


The obesity epidemic continues to be a dramatic problem in the developed world despite attempts to curtail its rise. Reducing energy intake and/or increasing energy expenditure can result in weight loss; however, if one returns to their poor lifestyle habits the previous weight is not only recuperated, but often surpassed.

We hypothesized that although a normal body weight may be achieved, the hypothalamic circuits controlling appetite and energy expenditure may not return to normal, at least in the same time-frame.

To this end, male and female 7-week old C57/BL6J mice were fed a high fat diet (HFD; 60% kcal from fat, 20% kcal from carbohydrates, 5.1 kcal/g) or standard rodent chow (3.1 % kcal from fat, 76% kcal from carbohydrates, 3.41 kcal/g) for 2 months. Then, half of the HFD group was returned to the normal chow diet (HFDCH). All mice were killed one month later, with a glucose tolerance test (GTT) being performed one week before. Hypothalmi were processed for real time PCR. At two months all HFD mice had gained significantly more weight than the chow mice. After the return to chow, HFDCH mice lost weight and after one month their weight was not different from chow mice. Although HFD increased fasting glucose in both sexes, only male HFD mice had an increased area under the curve in the GTT (P<0.001). Fasting glycemia and energy intake of HFDCH mice normalized one month after the diet changed. Females had higher hypothalamic mRNA levels of neuropeptide Y (NPY) and Agouti-related peptide (AgRP) than males (both P<0.0002), with HFD decreasing the expression of these neuropeptides in both sexes. The change from HFD to chow increased AgRP expression to control levels in both sexes. In females NPY mRNA returned to control levels, but in males NPY expression was only partially normalized. Proopiomelanocortin (POMC) mRNA levels were higher in males than females and decreased on the HFD only in males (P<0.004) and remained reduced one month after being changed to chow. In females there were no differences in POMC mRNA levels between dietary groups.

In conclusion, there is a clear sex difference in the response of hypothalamic metabolic neuropeptides to dietary changes. Although a normal weight is obtained, the hypothalamic metabolic control system, especially in males, remains altered. Thus, this could result in a more dramatic increase in weight gain if returned to a less healthy lifestyle.