The median eminence (ME) is a structure with an essential role in the hypothalamic regulation of energy balance, forming an interface between the central nervous system and the periphery which allows blood-borne endocrine and nutritional signals to interact with appetite-regulatory neurons. Within the ME resides a population of oligodendrocyte lineage cells which display a uniquely high degree of plasticity; Typically, populations of oligodendrocytes are long-lived, supporting their role in myelinating neuronal axons and providing trophic support to neurons. Meanwhile, oligodendrocyte progenitor cells (OPC) display continuous but modest proliferation, maintaining the OPC population and permitting the generation of new myelinating oligodendrocytes when needed. In contrast, OPCs in the ME demonstrate rapid and consistent proliferation, and continuously differentiate into new myelinating oligodendrocytes to replace mature ME oligodendrocytes which constitutively turn over. Despite the striking plasticity of this population, the functional relevance of ME oligodendrocyte lineage cells, and the mechanisms which regulate their unique physiology, have not yet been fully characterised.

The Blouet Laboratory has previously established, in mice, that ME oligodendrocyte lineage cell plasticity is modulated by nutritional status, and that oligodendrocytes and myelin accumulate in the ME during diet-induced obesity (DIO). The work presented in this thesis further characterises ME oligodendrocyte lineage cell physiology in DIO mice and demonstrates that changes in oligodendrocyte lineage cell plasticity occur in response to subacute episodes of high-fat feeding, prior to significant weight gain, and are associated with significant effects on whole-body energy balance.

ME oligodendrocytes were also previously demonstrated to express cognate receptors for a number of hormones associated with the regulation of energy balance. In particular, the expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is enriched in mature oligodendrocytes of the ME, pre-empting speculation that the oligodendrocyte lineage cells of the ME may be responsive to endogenous GIPR signalling. This thesis demonstrates that the genetic ablation of Gipr in oligodendrocytes is sufficient to blunt the accumulation of oligodendrocyte lineage cells in the ME during DIO, suggesting that GIPR signalling is an important mechanism in the regulation of ME oligodendrocyte lineage cell plasticity.

The mechanism explaining how the addition of GIPR agonism to GLP-1R agonist treatments for weight loss, to achieve dual incretin receptor agonism (IRA), can improve treatment efficacy has long been speculated to involve changes in central agonist signalling. As such, the possibility that GIPR signalling-mediated changes in ME oligodendrocyte plasticity could contribute to the improved weight loss efficacy of dual IRA therapies was investigated. The results presented herein indicate that oligodendrocyte GIPR signalling may indeed mediate the improved weight loss efficacy of dual IRA compared to GLP-1R agonism alone, in addition to regulating ME oligodendrocyte lineage plasticity during DIO more generally.

Collectively, this thesis highlights the importance of ME oligodendrocyte lineage plasticity to both the regulation of whole-body energy balance and the weight loss efficacy of dual IRAs in DIO.