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Studies suggest that body weight strongly influences the clinical progression rate of HD and thereby offers a valuable target for therapeutic interventions. Mutant huntingtin (mHTT) is ubiquitously expressed and could induce toxicity by directly acting in the peripheral tissues. We investigated the effects of selective expression of mHTT exon1 in fat body (FB; functionally equivalent to human adipose tissue and liver) using transgenic <jats:italic>Drosophila<\/jats:italic>. We find that FB-autonomous expression of mHTT exon1 is intrinsically toxic and causes chronic weight loss in the flies despite progressive hyperphagia, and early adult death. Moreover, flies exhibit loss of intracellular lipid stores, and decline in the systemic levels of lipids and carbohydrates which aggravates over time, representing metabolic defects. At the cellular level, besides impairment, cell death also occurs with the formation of mHTT aggregates in the FB. These findings indicate that FB-autonomous expression of mHTT alone is sufficient to cause metabolic abnormalities and emaciation <jats:italic>in vivo<\/jats:italic> without any neurodegenerative cues.<\/jats:p>","DOI":"10.1038\/s41598-019-46470-8","type":"journal-article","created":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T10:03:41Z","timestamp":1562925821000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Peripheral Expression of Mutant Huntingtin is a Critical Determinant of Weight Loss and Metabolic Disturbances in Huntington\u2019s Disease"],"prefix":"10.1038","volume":"9","author":[{"given":"Priya","family":"Lakra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumari","family":"Aditi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namita","family":"Agrawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,7,12]]},"reference":[{"issue":"6","key":"46470_CR1","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","volume":"72","author":"M MACDONALD","year":"1993","unstructured":"The Huntington\u2019s Disease Collaborative Research Group. 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