Elucidating the mechanisms by which short chain fatty acids (SCFA) reduce body weight may assist in the development of an effective weight control strategy. Dietary supplementation of acetate, propionate, butyrate or their admixture was shown to significantly inhibit the body weight gain induced by high-fat diet feeding. Supplementation of SCFAs caused significant changes in the expressions of G-protein coupled receptor 43 (GPR43) and GPR41 characterized by increases in the adipose tissue and reductions in the colon. Additionally, they influenced the bacterial community structure in feces, with a reduction in the proportion of Firmicutes and an increase in the proportion of Bacteroidetes. The effects of dietary SCFAs on the GPR expression and gut microbiota composition may further result in body weight reduction by enhancing triglyceride hydrolysis and FFA oxidation in the adipose tissue, promoting beige adipogenesis and mitochondrial biogenesis, and inhibiting chronic inflammation.

We report evidence of a detailed epigenetic modification of the leptin promoter and the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), which is closely associated with the leptin gene transcription in obesity. In the adipose tissue of diet induced obese (DIO) mice, methylation of the CpG island and the binding of methyl-CpG-binding domain protein 2 (MBD2) and DNA methyltransferases (DNMTs) at the leptin promoter are increased and RNA Pol II is decreased. Additionally, histones H3 and H4 are hypoacetylated, lysine 4 of histone H3 (H3K4) is hypomethylated and the binding of histone deacetylases (HDACs) 1, 2 and 6 is increased at the leptin promoter in the DIO mice. These modifications may serve a feedback role to maintain leptin concentrations within a normal range. The regulation of leptin transcriptional expression by n-3 PUFAs is mediated, at least in part, by epigenetic targets, such as MBD2 and histone modifications.

Plasma LDL levels and atherosclerosis both increase on a saturated fat-rich (SAT) diet. LDL cholesterol delivery to tissue may occur via uptake of the LDL particles or via selective uptake (SU), wherein cholesteryl ester (CE) enters cells without concomitant whole-particle uptake. It is not known how dietary fats might directly affect arterial LDL-CE uptake and whether SU is involved. Thus, mice that are relatively atherosclerosis resistant (C57BL/6) or susceptible to atherosclerosis (apoE -/-) were fed a chow or SAT diet and injected with double radiolabeled or fluorescent-labeled human LDL to independently trace LDL-CE core and whole-particle uptake, respectively. Our results show that a SAT diet increased contributions of SU to total arterial LDL-CE delivery in C57BL/6 and apoE -/-mice. The SAT diet increased plasma fatty acid and cholesterol levels; cholesterol, but not fatty acid, levels correlated with SU, as did the degree of atherosclerosis. Increased SU did not correlate with arterial scavenger receptor class B type I levels but paralleled increased lipoprotein lipase (LPL) levels and LPL distribution in the arterial wall. These studies suggest that arterial LDL-CE delivery via SU can be an important mechanism in vivo and that dietary influences on arterial LPL levels and atherogenesis modulate arterial LDL-CE delivery, cholesterol deposition, and SU.