Effect of high-fat diet on hypothalamic functions

Linehan, Victoria (2017) Effect of high-fat diet on hypothalamic functions. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The increased prevalence of high-fat food in modern society has led to an epidemic of overeating and obesity. High-fat diets are known to modulate homeostatic and reward pathways in the brain that regulate feeding, which may underlie caloric overconsumption. Such modulation may involve functional plasticity of feeding-related neurons including orexin and melanin-concentrating hormone (MCH) neurons of the lateral hypothalamus. However, how these neurons respond to high-fat diet at a cellular level and whether their responses precede obesity is incompletely understood. We used in vitro electrophysiology on acute brain slices from rats fed a high-fat, Western Diet (WD) or a standard chow to assess WD-induced plasticity of orexin and MCH neurons. We found that orexin neurons display dynamic responses to WD. Excitatory transmission to orexin neurons is potentiated as early as 1 day and 1 week of WD feeding. At the same time, we found that a novel activity-dependent presynaptic long-term depression occurs only in the WD condition in orexin neurons, which is mediated by mGluR5 and retrograde cannabinoid signaling. This LTD may be a homeostatic mechanism to limit overactivation of the orexin system. With longer feeding, these effects on excitatory transmission become attenuated while inhibitory transmission is increased, which would limit the excitability of orexin neurons. Contrastingly, WD induced a delayed activation of MCH neurons by 4 weeks of feeding through increased excitatory synaptic input and direct membrane depolarization due to an inhibition of the Na⁺/K⁺₋ATPase. The latter depends on the activity of cyclooxygenase and is mimicked by prostaglandin E₂, an inflammatory mediator. These changes are persistent and further exacerbated by prolonged feeding. Furthermore, this activation of MCH neurons underlies increased WD intake and weight gain, which likely contributes to diet-induced obesity. This is the first study to link excitation of feeding-related neurons with brain inflammation as a mechanism to explain high fat diet-induced weight gain. In summary, we have found that complex, time-dependent plasticity occurs in the lateral hypothalamus over the course of WD feeding. This plasticity likely affects food intake and weight gain, as well as other physiological functions of orexin and MCH neurons. Therefore, our study may provide valuable insights into developing treatments for obesity.

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