Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis

Abstract

There are multiple identified mechanisms involved in energy metabolism, insulin resistance and adiposity, but there are here-to-fore unsuspected metabolic factors that also influence these processes. Studies in animal models suggest important links between choline/1-carbon metabolism and energy homeostasis. Rodents fed choline deficient diets become hypermetabolic. Mice with deletions in one of several different genes of choline metabolism have phenotypes that include increased metabolic rate, decreased body fat/lean mass ratio, increased insulin sensitivity, decreased ATP production by mitochondria, or decreased weight gain on a high fat diet. In addition, farmers have recognized that the addition of a metabolite of choline (betaine) to cattle and swine feed reduces body fat/lean mass ratio. Choline dietary intake in humans varies over a > three-fold range, and genetic variation exists that modifies individual requirements for this nutrient. Although there are some epidemiologic studies in humans suggesting a link between choline/1-carbon metabolism and energy metabolism, there have been no controlled studies in humans that were specifically designed to examine this relationship.

Conflict of interest statement

Conflict of interest statement

Author’s conflict of interest disclosure: The author stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Figures

Figure 1. Hypothetical pathways for crosstalk between choline metabolism and insulin sensitivity

Available data suggest that there is metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis pathways. Though not yet proven to be the source of this crosstalk, several possible signaling pathways are influenced by choline or its metabolites. FGF21, fibroblast growth factor 21; IRS-2, insulin receptor substrate 2; PC, phosphatidylcholine; PPAR α, peroxisome proliferator-activated receptor α; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species; SAM,S-adenosylmethionine; SREBP1, sterol regulatory element-binding protein 1.

Figure 2. Genes that influence choline metabolism and dietary requirements

Choline is a precursor for formation of the neurotransmitter acetylcholine, it can be phosphorylated to form phosphatidylcholine, or it can be oxidized to form betaine (catalyzed by choline dehydrogenase; CHDH). Betaine is used as a methyl donor in the formation of methionine (catalyzed by betaine homocysteine methyltransferase, BHMT). 5-methyltetrahydrofolate is an alternative methyl-group donor for the formation of methionine (a critical step in the formation of methyltetrahydrofolate is catalyzed by methylene tetrahydrofolate dehydrogenase; MTHFD). Methionine is a precursor ofS-adenosylmethionine, which in turn can be used to form phosphatidylcholine (catalyzed by phosphatidylethanolamine methyltransferase; PEMT). Homocysteine is a precursor for cysteine synthesis. Genetic polymorphisms in CHDH, PEMT and MTHFD1 have been identified which increase the dietary requirement for choline. In mice withChdh genes deleted, mitochondrial function is abnormal; with Bhmt deleted mice have abnormal body fat pads and energy metabolism.

Figure 3. Bhmt−/− mice have reduced fat pad weight

GWAT, gonadal white adipose tissue and IWAT, inguinal white adipose tissue were harvested from Bhmt+/+ (black) andBhmt−/− (white) mice. **p<0.01. From reference [35] with permission.

Figure 4. Men with a functional SNP in CHDH (rs12676) have decreased ATP concentrations reflecting mitochondrial dysfunction

Men who were heterozygous or homozygous for the rs12676 variant T allele have reduced ATP concentrations in their sperm. N=17 (GG), 18 (GT) and 5 (TT).* indicates difference from GG by ANOVA and Tukey-Kramer HSD, p-value