Fat synthesis and adiposity regulation in Caenorhabditis elegans

Abstract

Understanding the regulation of fat synthesis and the consequences of its misregulation is of profound significance for managing the obesity epidemic and developing obesity therapeutics. Recent work in the roundworm Caenorhabditis elegans has revealed the importance of evolutionarily conserved pathways of fat synthesis and nutrient sensing in adiposity regulation. The powerful combination of mutational and reverse genetic analysis, genomics, lipid analysis, and cell-specific expression studies enables dissection of complicated pathways at the level of a whole organism. This review summarizes recent studies in C. elegans that offer insights into the regulation of adiposity by conserved transcription factors, insulin and growth factor signaling, and unsaturated fatty acid synthesis. Increased understanding of fat-storage pathways might lead to future obesity therapies.

Figure I

Fat staining of wild-type C. elegans. (a) Sudan Black staining of a fixed L4-stage larva. Black-stained fat droplets are visible in the intestinal and hypodermal cells. (b) Nile Red staining of a live L4-stage larva. Intestinal gut granules fluoresce red. In both pictures, anterior is to the left.

Figure 1

Fatty acid synthesis pathways in C. elegans. (a) De novo synthesis of polyunsaturated fatty acids (PUFAs) begins with acetyl-CoA and utilizes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Dietary fatty acids such as palmitic acid (16:0) can also enter the pathway and be converted to PUFAs by various desaturase and elongase activities. (b) Monomethyl branched-chain fatty acid synthesis uses a branched-chain primer as a substrate, FAS and specialized elongase activities to synthesize C15:iso and C17:iso, which are essential for growth. Fatty acid nomenclature: X:Yn-Z, fatty acid chain of X carbon atoms and Y methylene-interrupted cis double bonds; Z indicates the position of the terminal double bond relative to the methyl end of the molecule. Gene activities: FAT-1, omega-3 desaturase; FAT-2, Δ12 desaturase; FAT-3, Δ6 desaturase; FAT-4, Δ5 desaturase; FAT-5, Δ9 desaturase; FAT-6, Δ9 desaturase; FAT-7, Δ9 desaturase; ELO, fatty acid elongase; LET-767, 3-ketoacyl-CoA reductase.

Figure 2

Proposed pathways influencing adiposity in C. elegans. Sensory neurons secrete (a) serotonin, (b) insulin and (c) TGF-β in response to nutritional cues. These signals are perceived by receptors (blue boxes), and signals are transduced by kinases and other signaling pathways (grey boxes). At least four transcription factors (pink ovals), in addition to the transcriptional mediator MDT-15 (green), are required for efficient transcription of the Δ9 desaturase genes fat-5, fat-6 and fat-7. These and other fat-synthesis genes (purple boxes) promote fat storage, whereas expression of genes encoding β-oxidation enzymes in mitochondria (brown oval) promote increased fat oxidation, culminating in decreased fat stores. Experiments performed to determine the downstream pathway from serotonin used exogenous serotonin. Abbreviations: TGF-β, transforming growth factor-β; SREBP, sterol regulatory element-βinding protein; GPCR, G-protein-coupled receptor; TF, transcription factor; NHR, nuclear hormone receptor.

Figure 3

Schematic representation highlighting the relationship between fatty acid synthesis and fatty acid oxidation in C. elegans. Dietary carbohydrates that are not immediately used are converted to acetyl-CoA, which can be used to synthesize fatty acids. Along with dietary fatty acids, these molecules can be stored as triacylglycerides (TAGs) for future use. Fatty acids negatively regulate acetyl-CoA carboxylase (ACC) by feedback inhibition, which results in reduced levels of malonyl-CoA. This reduction increases the activity of carnitine palmitoyl transferase (CPT), which is sensitive to levels of malonyl-CoA, enabling increased uptake of fatty acids into mitochondria (brown oval), where they are oxidized. In C. elegans, dauer-stage larvae do not feed and rely on fat stores for energy. Unlike most other animals, they possess enzymes of the glyoxylate shunt, which enables the fat breakdown product acetyl-CoA to be converted into carbohydrates via gluconeogenesis. Key lipid synthesis enzymes are depicted as pink ovals, and metabolic pathways of multiple enzymatic steps are depicted as gray ovals. Abbreviations: FAS, fatty acid synthase; MUFAs, monounsaturated fatty acids.