Profound weight loss induces reactive astrogliosis in the arcuate nucleus of obese mice

Luke Harrison, Katrin Pfuhlmann, Sonja C. Schriever, Paul T. Pfluger

Astrocytes and microglia respond to noxious stimuli by a process known as reactive gliosis (RG). RG is characterized by morphological changes such as increased cell size, enlarged, lengthened processes, and an increase in proliferation. Previously, in mice fed a high-fat diet (HFD) the number of reactive astrocytes and microglia in the arcuate nucleus (ARC) was increased. Harrison et al. have found that mice which are chronically obese after 22 weeks of HFD feeding display RG levels in the ARC comparable to levels seen in age-matched chow fed mice. Furthermore, profound weight loss results in an increase in ARC related astrocytic RG. However, whether or not reactive gliosis plays a role in chronic obesity, or rather in the acute adaptation to the dietary environment, remains to be fully understood.

Objective: Obesity has been linked to an inflammation like state in the hypothalamus, mainly characterized by reactive gliosis (RG) of astrocytes and microglia. Here, using two diet models or pharmacological treatment, we assessed the effects of mild and drastic weight loss on RG, in the context of high-fat diet (HFD) induced obesity.

Methods: We subjected HFD-induced obese (DIO) male C57BL/6J mice to a weight loss intervention with a switch to standard chow, calorie restriction (CR), or treatment with the Glp1 receptor agonist Exendin-4 (EX4). The severity of RG was estimated by an ordinal scoring system based on fluorescence intensities of glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1 positive (Iba1), cell numbers, and morphological characteristics.

Results: In contrast to previous reports, DIO mice fed chronically with HFD showed no differences in microglial or astrocytic RG, compared to chow controls. Moreover, mild or profound weight loss had no impact on microglial RG. However, astrocyte RG was increased in CR and EX4 groups compared to chow fed animals and strongly correlated to body weight loss. Profound weight loss by either CR or EX4 was further linked to increased levels of circulating non-esterified free fatty acids.

Conclusions: Overall, our data demonstrate that in a chronically obese state, astrocyte and microglial RG is indifferent from that observed in age-matched chow controls. Nonetheless, profound acute weight loss can induce astrocyte RG in the hypothalamic arcuate nucleus, possibly due to increased circulating NEFAs. This suggests that astrocytes may sense acute changes to both the dietary environment and body weight.