Sasaki T, Numano R, Yokota-Hashimoto H, Matsui S, Kimura N, Takeuchi H, KitamuraT Sasaki T, Yokota-Hashimoto H, Matsui S, Kitamura T (IMCR, Gunma Univ.) Numano R, Kimura N (Toyohashi University of Technology) Takeuchi T（Yokohama City Univ.）
A high-fat diet (HFD) causes obesity by promoting excessive energy intake, and simultaneously, by disturbing the timing of energy intake. Restoring the feeding pattern is sufficient to prevent HFD-induced obesity in mice. However, the molecular mechanism(s) underlying HFD-induced feeding pattern disturbances remain elusive. Saturated fatty acids activate microglia and cause hypothalamic inflammation. Activated microglia cause neuroinflammation, which spreads via inflammatory cytokines and gap-junction hemichannels. However, the role of gap-junction hemichannels in HFD-induced obesity remains unaddressed. We used a novel, central-acting connexin inhibitor, INI-0602, which has high affinity for gap junction hemichannels and does not affect the induction of inflammatory cytokines, and addressed the question. We found that HFD feeding induced acute hyperphagia, mainly during the light cycle. Feeding pattern disturbances were more pronounced in mice that consumed the HFD with very high SFAs than in mice that consumed the HFD with elevated SFAs. When INI-0602 was administered before the HFD was introduced, it blocked the feeding pattern disturbance, but not locomotor activity disturbances; moreover, it prevented subsequent diet-induced obesity. Therefore, we propose that SFAs in HFDs played a major role in disrupting feeding patterns in mice. Moreover, the feeding pattern disturbance required the function of central, gap junction hemichannels at the initiation of a HFD. Preventing the occurrence of a feeding pattern disturbance by blocking the hemichannel pathway was associated with the prevention of the HFD-induced obesity in mice.
A central-acting connexin inhibitor, INI-0602, prevents high-fat diet-induced feeding pattern disturbances and obesity in mice. Sasaki T, Numano R, Yokota-Hashimoto H, Matsui S, Kimura N, Takeuchi H, KitamuraT. Mol Brain 11:28, 2018