Abstract
Betaine-homocysteine methyltransferase (BHMT) catalyzes the transfer of methyl-groups from betaine to homocysteine (Hcy) producing methionine and dimethylgycine. In this work, we characterize Bhmt wildtype (WT) and knockout (KO) mice that were fully backcrossed to a C57Bl6/J background. Consistent with our previous findings, Bhmt KO mice had decreased body weight, fat mass and adipose tissue weight compared to WT. Histological analyses and gene expression profiling indicate that adipose browning was activated in KO mice and contributed to the adipose atrophy observed. BHMT is not expressed in adipose tissue but is abundant in liver, thus, a signal must be originating from the liver that modulates adipose tissue. We found that, in Bhmt KO mice, homocysteine-induced endoplasmic reticulum (ER) stress, with activation of hepatic transcription factor cyclin AMP response element binding protein (CREBH), mediated an increase in hepatic and plasma concentrations of fibroblast growth factor 21 (FGF21), which is known to induce adipose browning. CREBH binds to the promoter regions of FGF21 to activate its expression. Taken together, our data indicate that deletion of a single gene in one-carbon metabolism modifies adipose biology and energy metabolism. It would be interesting to determine whether people with functional polymorphisms in BHMT exhibit a similar adipose atrophy phenotype.
Competing Interest Statement
The authors have declared no competing interest.
List of abbreviations
- CIDEA
- Cell death-inducing DFFA-like effector A
- ATF3
- Activating Transcription Factor 3
- BHMT
- Betaine Homocysteine-S-Methyltransferase
- BAT
- Brown adipose tissue
- CHOP
- c/EPB homologous protein
- CREBH
- Cyclic AMP response element binding protein
- H FGF21
- Fibroblast Growth Factor 21
- Hcy
- Homocysteine
- PCG-α
- Peroxisome Proliferator-activated receptor gamma coativator 1-alpha
- SAM
- S-adenosyl methionine
- UCP1
- Uncoupling Protein 1
- WAT
- White adipose tissue