Endocrine Abstracts

Background: Human cohorts and animal models provide compelling evidence suggesting the role of vitamin B12 in modulating the risk of diabetes and adiposity via developmental programming. We recently demonstrated that neonates born to mothers with low B12 levels in pregnancy have adverse cord blood lipid profile and in vitro studies in human adipocytes with low B12 showed increased cholesterol biosynthesis. Therefore, we hypothesized that vitamin B12 deficiency may play an important role in the regulation of adipogenesis. We chose adipocytes as an in-vitro model system as they undergo several cycles of differentiation and maturation, mimicking in-vivo intergenerational effect (pregnancy-offspring) and investigated the role of vitamin B12 deficiency on adipogenesis.

Methods: Primary human pre-adipocytes were cultured and differentiated in various B12 concentrations (1) Control: (B12 – 500 nM); (2) Low B12 (B12 – 0.15 nM) (3) No B12: (B12 – 0 nM). Maternal venous blood samples (n=91) and adipose tissue (n=42) were collected at delivery.

Results: Adipocytes cultured in B12 deficient conditions showed increased lipid accumulation and triglyceride levels. In our clinical study, mothers with low B12 status had higher BMI and adverse lipid profile. Gene expression of adipogenic regulators (PPARγ, CEBPα, RXRα), lipid coating protein (perilipin), lipogenesis (FASN, ACC1) and development-related genes (Zfp423, EZH2, WISP2) were altered in adipocytes cultured in B12 deficient conditions and in adipose tissue from mothers with low B12. Expression of anti-adipogenic microRNAs (miR-27b and miR-195a targeting PPARγ and Zfp423, respectively) were down-regulated in adipocytes cultured in B12 deficient conditions.

Conclusion: Our study highlights that low B12 enhances adipogenesis and triggers specific microRNAs. Thus suggesting B12 deficiency alters adipocyte commitment and differentiation via epigenetic alterations leading to the development of obesity and insulin resistance in later life.