Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2013

RAB-Like 2 (RABL2) is a critical regulator of male fertility and fatty acid metabolism (#189)

Jennifer Lo 1 , Tony Tiganis 2 , Zane Andrews 3 , Matthew Watt 3 , Moira O'Bryan 1
  1. Department of Anatomy & Developmental Biology, Monash University, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia
  3. Department of Physiology, Monash University, Victoria, Australia

Recently we have identified the previously uncharacterized small GTPase RABL2 as an essential regulator of male fertility [1]. Specifically we showed that RABL2 cycles between a GTP-bound active state and a GDP-bound inactive state. In the active state RABL2 binds to a set of effector proteins, which it delivers into the growing sperm tail compartment. Rabl2 mutant male animals are sterile as a consequence of decreased effector protein content within sperm.

More surprisingly we have also found that Rabl2 mutant mice (either carrying point mutation or null alleles) develop steatosis (fatty liver) and ultimately become over-weight and insulin resistant. DEXA analysis revealed that weight gain is due to increasing adiposity and indirect calorimetry suggests that decreased energy expenditure contributes to weight gain in adults. Additional data however, strongly suggests that the primary defect is a shift in hepatocyte metabolism balance towards a pro-lipogenic phenotype. Specifically, Rabl2 mutant animals show an abnormal accumulation of lipid droplets from 4 weeks-of-age i.e. well before the detection of statistically significant differences in body weight at 10 weeks-of-age. Further, 4 week-old mouse livers show elevated expression levels of Srebp1c, Scd1 and Gpam, and a decreased capacity to oxidise fatty acids. This phenotype becomes progressively worse with increasing age and by 12 weeks-of-age hepatocytes exhibit elevated DAGs and TAGs.

In an effort to identify the biochemical function of RABL2 within the liver we have identified effector proteins using a proteomic approach. Pathway analysis indicates a strong association between RABL2 effector proteins and mitochondrial and peroxisome fatty acid metabolism. Thus, we hypothesis that RABL2 is involved in the transport of metabolically important proteins into either mitochondria or peroxisomes or in the movement of whole organelles.

  1. Lo JC, Jamsai D, O'Connor AE, Borg C, Clark BJ, et al. (2012) RAB-like 2 has an essential role in male fertility, sperm intra-flagellar transport, and tail assembly. PLoS Genet 8: e1002969.