Obesity results in chronic low-grade inflammation of several organs, including the liver, muscle, and adipose tissue, as well as the hypothalamus (8
). Inflammation is thought to exacerbate metabolic abnormalities by disrupting homeostatic pathways within target tissues (8
). For example, infiltration of adipose tissue by macrophages has been linked to the development of insulin resistance (8
). Inflammation is also thought to be increased in the hypothalamus of obese rodents and may promote food intake and hypertension (9
). Although inflammation in the hypothalamus is thought to be harmful to neuronal function, little is known about the effects of a high-fat diet (HFD) on glia — nonneuronal cells that are more abundant in the central nervous system than neurons, provide support and nutrition to neurons (astrocytes), and mediate inflammation in the brain (microglia). Moreover, it is not clear how closely hypothalamic inflammation mirrors peripheral inflammation. In their study in this issue of the JCI
, Thaler et al. found some interesting differences (Figure and ref. 13
). In liver and adipose tissue, inflammatory markers increase in number and magnitude slowly over the course of weeks to months in rats fed HFD (8
). In contrast, Thaler et al. found that inflammatory gene expression increased in the arcuate nucleus of rats within one day of initiating a HFD (13
). This initial spike in inflammation in the hypothalamus occurred in the absence of weight gain and coincided with increased gliosis, the process whereby astrocytes and microglia are activated and proliferate in response to a brain insult, as measured by the expression of microglial and astrocytic genes (Figure ). The gene expression patterns were corroborated by immunohistochemistry, which showed an increase in the number and size of reactive glia. However, the rise in inflammatory gene expression and gliosis subsided within a week and reappeared only after continued prolonged exposure to HFD. This biphasic inflammatory response to a HFD was unique to the arcuate nucleus; it was not observed in the liver, adipose tissue, and other regions of the brain. Similar patterns of inflammation and gliosis were also observed in mice fed a HFD.
What are the consequences of arcuate nucleus inflammation and gliosis in rodents fed a HFD? Thaler et al. looked for evidence of neuronal injury, particularly in POMC neurons within the arcuate nucleus (13
). At seven days after a HFD was initiated, they found that many POMC neurons displayed an increase in expression of Hsp70, a chaperone protein that is induced in response to various stressors and neuronal injury. There was also evidence of increased autophagy within POMC neurons after 20 weeks on a HFD. After 8 months on a HFD, the number of POMC neurons within the arcuate nucleus was reduced by 25%.
The rodent studies performed by Thaler et al. (13
) provide a time line of injury to the arcuate nucleus in response to a HFD. In particular, the early induction of inflammation and reactive gliosis, together with evidence of neuronal stress within one week, suggest that the arcuate nucleus is injured acutely and that perhaps this early insult may be linked to the development of an abnormal energy balance and obesity. Thaler et al. then extended these findings by studying brain images in patients (13
). They found that body mass index, a measure of fat content, was proportional to T2 signal in the hypothalamus by MRI. T2-weighted MRI is particularly sensitive for identifying brain lesions, including inflammation, gliosis, and edema. This finding raises the possibility that obesity increases hypothalamic gliosis (20
), but further studies in humans are required to ascertain whether this is indeed the case and whether hypothalamic inflammation and injury occur in the arcuate nucleus, as in rodents.