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Previously, increased acute food intake following the chemical reduction of hepatic fatty acid oxidation and ATP levels was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a hepatocyte PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male, but not female, mice had a 70% greater high-fat\/high-sucrose (HFHS) diet-induced weight gain compared to wildtype (WT) mice (p &lt; 0.05). The greater weight gain was associated with altered feeding behavior and lower activity energy expenditure during the HFHS diet in LPGC1a males. WT and LPGC1a mice underwent sham surgery or HBV to assess whether vagal signaling was involved in the HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p &lt; 0.05) in male WT mice, but not LPGC1a mice. These data demonstrate a sex-specific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need for a more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.<\/jats:p>","DOI":"10.3390\/nu13082596","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T11:12:52Z","timestamp":1627470772000},"page":"2596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7046-3623","authenticated-orcid":false,"given":"E. Matthew","family":"Morris","sequence":"first","affiliation":[{"name":"Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"},{"name":"Center for Children\u2019s Healthy Lifestyle and Nutrition, Children\u2019s Mercy Hospital, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7029-4727","authenticated-orcid":false,"given":"Roberto D.","family":"Noland","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael E.","family":"Ponte","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle L.","family":"Montonye","sequence":"additional","affiliation":[{"name":"Department of Nutrition & Exercise Physiology, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie A.","family":"Christianson","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4667-4057","authenticated-orcid":false,"given":"John A.","family":"Stanford","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Miles","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2014Division of Endocrinology and Metabolism, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew R.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John P.","family":"Thyfault","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"},{"name":"Center for Children\u2019s Healthy Lifestyle and Nutrition, Children\u2019s Mercy Hospital, Kansas City, MO 64108, USA"},{"name":"Department of Internal Medicine\u2014Division of Endocrinology and Metabolism, University of Kansas Medical Center, Kansas City, KS 66160, USA"},{"name":"Kansas City VA Medical Center-Research Service, Kansas City, MO 64128, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1001\/jama.2020.14590","article-title":"Trends in Obesity Prevalence by Race and Hispanic Origin\u20141999\u20132000 to 2017\u20132018","volume":"324","author":"Ogden","year":"2020","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1161\/CIRCULATIONAHA.111.087213","article-title":"Energy balance and obesity","volume":"126","author":"Hill","year":"2012","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/oby.2008.320","article-title":"Influence of Weekend Lifestyle Patterns on Body Weight","volume":"16","author":"Racette","year":"2008","journal-title":"Obesity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1475-2891-5-29","article-title":"The effect of the Thanksgiving Holiday on weight gain","volume":"5","author":"Hull","year":"2006","journal-title":"Nutr. 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