{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:04:33Z","timestamp":1791198273326,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["1\u201019\u2010JDF\u2010081"],"award-info":[{"award-number":["1\u201019\u2010JDF\u2010081"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Mutations in NHE6 (human gene name\n                      <jats:italic>SLC9A6<\/jats:italic>\n                      ) lead to the rare X\u2010linked disorder Christianson syndrome (CS) characterized by intellectual disability, autism and ataxia. NHE6 is a Na\n                      <jats:sup>+<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      exchanger that regulates pH and ionic equilibria across endosomal membranes in a variety of tissues, although its non\u2010neuronal role is understudied. A common co\u2010morbidity in CS is low body weight, with body mass index in the 3\u20135th percentile range. In the present study, we use a\n                      <jats:italic>\n                        Nhe6\n                        <jats:sup>KO<\/jats:sup>\n                      <\/jats:italic>\n                      mouse model of CS to demonstrate a role for NHE6 in fat accumulation and glucose homeostasis. On both chow and a high\u2010fat diet,\n                      <jats:italic>\n                        Nhe6\n                        <jats:sup>KO<\/jats:sup>\n                      <\/jats:italic>\n                      mice displayed lower body weight and decreased fat accumulation in adipose tissue. By contrast, glycogen accumulation was strongly increased in liver of\n                      <jats:italic>\n                        Nhe6\n                        <jats:sup>KO<\/jats:sup>\n                      <\/jats:italic>\n                      mice on a high\u2010fat diet. Knockdown of NHE6 (NHE6 KD) in 3T3L1 adipocytes resulted in smaller lipid droplets, pointing to a cell autonomous role in fat accumulation. NHE6 KD adipocytes also exhibit dysregulation of insulin\u2010responsive uptake of fatty acids, glucose and Fe\/transferrin, as well as the cell surface translocation of the corresponding transporters. Furthermore, we observed selective downregulation of key components of the insulin signalling pathway that could be restored using the Na\n                      <jats:sup>+<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      exchanger mimetic monensin or the V\u2010ATPase inhibitor bafilomycin, pointing to pH dysregulation as the underlying defect. These findings establish NHE6 as a novel contributor to energy metabolism with implications for CS patients.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70113-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            NHE6 is an endosomal Na\n                            <jats:sup>+<\/jats:sup>\n                            \/H\n                            <jats:sup>+<\/jats:sup>\n                            exchanger mutated in Christianson syndrome.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>Nhe6<\/jats:italic>\n                            null mice accumulate less fat and weigh less than control animals.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In adipocytes, NHE6 knockdown reduces insulin\u2010stimulated fatty acid and glucose uptake.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>NHE6 exerts proteostatic control over multiple components of the insulin signalling pathway.<\/jats:p>\n                        <\/jats:list-item>\n          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