The Christianson syndrome protein, sodium hydrogen exchanger isoform 6, is required for fat accumulation.

Mutations in NHE6 (human gene name SLC9A6) lead to the rare X-linked disorder Christianson syndrome (CS) characterized by intellectual disability, autism and ataxia. NHE6 is a Na⁺/H⁺ exchanger that regulates pH and ionic equilibria across endosomal membranes in a variety of tissues, although its non-neuronal role is understudied. A common co-morbidity in CS is low body weight, with body mass index in the 3-5th percentile range. In the present study, we use a Nhe6^KO mouse model of CS to demonstrate a role for NHE6 in fat accumulation and glucose homeostasis. On both chow and a high-fat diet, Nhe6^KO mice displayed lower body weight and decreased fat accumulation in adipose tissue. By contrast, glycogen accumulation was strongly increased in liver of Nhe6^KO mice on a high-fat 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-responsive 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⁺/H⁺ exchanger mimetic monensin or the V-ATPase 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. KEY POINTS: NHE6 is an endosomal Na⁺/H⁺ exchanger mutated in Christianson syndrome. Nhe6 null mice accumulate less fat and weigh less than control animals. In adipocytes, NHE6 knockdown reduces insulin-stimulated fatty acid and glucose uptake. NHE6 exerts proteostatic control over multiple components of the insulin signalling pathway.