ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Cell Metabolism 2019;30:952–962. e5.

These authors report that high-fat diet (HFD) in mice induces a dynamic increase in uncoupling protein 2 (Ucp2) mRNA expression in hypothalamic microglia. Ucp2 is required for HFD-induced mitochondrial changes in hypothalamic microglia and for HFD-induced inflammation, obesity, and POMC synaptic plasticity.

The brain plays a major role in the regulation of feeding and whole-body metabolism. This study focused on the brain’s glia cells, rather than neurons, and shows a fundamental role for mitochondrial dynamics in microglia cells and their response to HFD.

It was known that HFD triggers microglia activation and hypothalamic inflammation as early as 3 days after HFD exposure, before changes in body weight occur. Here, they find that HFD induce a rapid and transient increase in Ucp2 mRNA expression together with changes in mitochondrial dynamics.

Ucp2 is a mitochondrial protein, which plays a critical role in mitochondrial function, including control of reactive oxygen species (ROS) generation and fuel utilization. Ucp2 has been implicated in the regulation of the activity of several hypothalamic neuronal populations involved in the control of energy and glucose homeostasis. It is highly expressed in activated microglial cells, and has also been implicated in mediating the energetic processes of microglia activation states in neuro-inflammation. Here, selective deletion of Ucp2 in microglia protected mice from HFD-induced obesity, showing decreased feeding and increased energy expenditure, associated with changes in the synaptic input organization and activation of the anorexigenic hypothalamic POMC neurons and astrogliosis. In peripheral macrophages, Ucp2 is required for mitochondrial oxidation of glutamine, while in hypothalamic NPY/AgRP neurons, Ucp2 promotes the metabolic shift from glucose oxidation to fatty acid oxidation during starvation.

In summary, this study shows that the combination of high glucose/high fat diet induces changes in microglial mitochondria dynamics and function via Ucp2. These mitochondrial changes are critical for microglia activation and neuro-inflammation that ultimately affect the susceptibility to diet-induced obesity.