The Acyltransferase Transmembrane Protein 68 Promotes Neutral Lipid Storage in Mouse Adipocytes

Transmembrane protein 68 (TMEM68) is a recently identified TAG synthase that is highly expressed in the brain and regulates central nervous lipid homeostasis. The global deficiency of TMEM68 in mice causes reduced adipose tissue mass indicating a role in energy homeostasis. In this study we further explored the role of TMEM68 in adipocyte TAG metabolism and whole-body energy metabolism. We show that TMEM68 deficient mice exhibit a delay in fat mass gain with reduced adipocyte size and TAG levels starting between 3 and 4 weeks of age. This is accompanied by reduced serum leptin levels and impaired glucose tolerance but unchanged cold tolerance. While TMEM68 deficient mice were fully responsive to pharmacological lipolytic stimulation, they failed to maintain plasma fatty acid levels upon fasting. Assessment of in vitro differentiated adipocytes confirmed TMEM68 as a positive regulator of adipocyte TAG storage and revealed an additional function in regulating adipocyte glycerophospholipids and polyunsaturated fatty acids. In summary, our data indicate that TMEM68 functions beyond brain lipid metabolism in regulating adipocyte lipids and whole-body energy homeostasis.