ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Endocrinology. 2018 Jan 1;159(1):368-387

Hypothalamic inflammation has been linked to the development and progression of obesity and its sequelae. Obesity in rodents and humans is associated with gliosis of the arcuate nucleus, a key hypothalamic region for the regulation of energy homeostasis and adiposity. Gliosis, the activation of astrocyte and microglial cell populations, is a hallmark of central nervous system injury and is detectable using either immunohistochemistry or in vivo magnetic resonance imaging (MRI). The activation of the hypothalamic inflammatory processes and gliosis depends not only on weight gain but also on the diet inducing this weight gain and the early nutritional status. A high fat diet in mice leads to increased inflammation, increased oxidative damage, decreased antioxidant enzymes activity and levels, changes in the Krebs cycle enzyme activities, and inhibition of mitochondrial respiratory chain complexes in the brain structures. In addition to this the impairment of intracellular and epigenetic mechanisms, such as hypothalamic autophagy and changes in the methylation pattern of certain genes, have been implicated in susceptibility to diet induced obesity. The above study assessed the impact of neonatal overnutrition on astrocyte response in Wister rats. Although the Wistar rats started to accumulate excessive fat mass as early as postnatal day (PND) 10 there was no increase in hypothalamic cytokine levels, markers of astrocytes or microglia, or inflammatory signaling pathways were observed. Signs of hypothalamic gliosis and inflammation were found in overweight PND 150 male rats, including an increase in the number of astroglia, increased levels of TNFa and activation of JNK. Females were not overweight at this age and showed no signs of hypothalamic inflammation/gliosis. Thus, not only is postpubertal weight/adiposity gain different in males and females in response to early overnutrition, but the central inflammatory response also differs. Estrogens are known to be protective against excess weight gain, and ovariectomy of postpubertal females results in weight gain and increased inflammation and therefore this might explain the difference in males and females. The inflammation and astrogliosis in the hypothalamus were associated with an increase in the level of fatty acids in males and not in females. Free fatty acids are known to induce neuroinflammation, endoplasmic reticulum stress, and dysregulation of neuropeptide synthesis. These observations suggest that neonatal overnutrition may also lead to hypothalamic inflammation possibly due to the increased levels of fatty acids and that oestrogens might be protective in females. Some of these protective effects of estradiol could be mediated through astrocytes. Further understanding of the differential responses of males and females to nutritional challenges is necessary to develop specific treatments for obesity according to sex.