**5. Conclusions**

In conclusion, our studies demonstrated that 5xFAD mice were more susceptible to HFD-induced metabolic disorders and that HFD could exacerbate stress on AD-related neuropathological and neuroinflammatory pathways. Altogether, our data sugges<sup>t</sup> that targeting metabolic dysfunctions caused by high dietary fat intake can ameliorate AD symptoms via e ffects on insulin signaling, neuroinflammation, Aβ deposition, and microglia activation in the hippocampus.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2072-6643/12/10/2977/s1, Figure S1: Study Design, Figure S2: Indirect calorimetry during fasting/refeeding challenge in male 5xFAD and WT mice fed NCD, Figure S3: 5xFAD mice fed normal chow diet exhibited age-dependent sexually dimorphic effects on body weight maintenance., Figure S4: Indirect calorimetry during fasting/refeeding challenge in male 5xFAD and WT mice fed high-fat diet (HFD), Figure S5: Heatmap of Nanostring pathway scores of 5xFAD mice on NCD versus HFD.

**Author Contributions:** Conceptualization, A.M.R., H.R., A.L.O.; methodology, A.M.R., H.R., A.L.O., A.C.E., P.B.L., A.P.T.; data curation, A.M.R., A.P.T., P.B.L., A.C.E.; formal analysis, A.M.R., A.P.T.; visualization, A.M.R.; investigation, A.M.R.; resources, H.R., A.L.O., A.C.E.; writing—original draft preparation, A.M.R. and H.R.; writing—review and editing, A.M.R. and H.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by Indiana University Multi-Center Collaborative Award (H. Ren, A. Oblak), NIH R00DK098294, NIH R01DK120772, P&F gran<sup>t</sup> from P30DK097512 and UL1TR002529, and Showalter Scholarship (H. Ren); Paul and Carole Stark Fellowship award, and Diabetes and Obesity Research Training award T32DK064466 (A. Reilly).

**Acknowledgments:** We would like to thank Indira Medina-Rodriguez (senior technical applications scientist from NanoString) for excellent technical support, Gary Landreth for critically reviewing the manuscript, Cynthia Ingraham, Christopher Lloyd, Deborah Baker, Shijun Yan, and Jason Conley for their help in collecting samples, Shijun Yan for assisting with GTT, Natalie Stull for assisting with indirect calorimetry measurements, Giedre Turner for 16S rRNA sequencing, Kara Orr for assisting with echoMRI scans, and Courtney Jewett for manuscript editing.

**Conflicts of Interest:** The authors declare no conflict of interest.
