Lipids have diverse functions and play a critical role in developmental processes. It is well known that lipids are essential in development, and perturbations in the regulation of membrane lipid metabolism cause early embryonic lethality. TMEM161B is a highly conserved 9-transmembrane domain protein that is known to play a role in modulating ion channels in development. Previous studies have shown that murine whole-body deletion of Tmem161b is perinatally lethal; therefore, we utilised an includible knockout model to explore the functional role of TMEM161B (Tmem161b-/-) in adult mice. Following tamoxifen-induced deletion, Tmem161b-/- had a rapid reduction in body weight (>18%) that necessitated euthanasia. This coincided with a striking 78% reduction in fat mass and increased adipose tissue lipolysis. Therefore, we rationalised that TMEM161B may play a role in regulating adipocyte metabolism.
To delineate the cell-autonomous role of TMEM161B, we utilised CRISPR/Cas9 gene editing in 3T3-L1 cells and found no alterations in adipocyte differentiation but rather increased fatty acid β-oxidation and respiration in mature adipocytes. Further to this, we generated an adipocyte-specific knockout mouse model (Tmem161bADIPOQ) by crossing Tmem161bflox/flox mice with Adiponectin-Cre to assess the relevance of these observations in a pre-clinical model of obesity. In contrast to our whole-body knockout observations, Tmem161bADIPOQ mice exhibited a mild reduction in body mass but no differences in adiposity or adipose tissue lipolysis. Tmem161bADIPOQ mice had increased whole-body expenditure and mild improvements in insulin sensitivity; however, this did not alter whole-body substrate utilisation or glucose tolerance. Together, this suggests that adipose-specific deletion of TMEM161B does not explain the severe adipose tissue loss observed in the whole-body knockout mouse model. Intriguingly, deletion of Tmem161b in murine hepatocytes (Tmem161bflox/flox X Albumin-Cre mice) partially phenocopied the weight loss observed in whole-body Tmem161b-/-. Ongoing studies aim to delineate how hepatocyte Tmem161b deletion regulates adiposity in mice.