Caenorhabditis elegansDBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling

Abstract

Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL-1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.

LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes

“…In C. elegans , LRIG/SMA-10 is reported to promote normal body size through BMP signaling 12 . Given that several BMP mutants have been reported to be defective in lipid homeostasis 34 , 35 , we hypothesized that defective lipid homeostasis could be a general trait of BMP mutants, including mutants for LRIG/sma-10 . As a BMP pathway-independent control for short body length, we included the cuticle collagen mutant dpy-5(e907) in our analysis 43 .…”

“…In this process, BMP signaling is involved in the commitment of mesenchymal stem cells into preadipocytes 30 , 31 , as well as in the choice between white or brown/beige adipocyte differentiation and adipocyte size 32 . C. elegans , on the other hand, lacks dedicated adipocytes; 33 however, evidence suggests that BMP signaling may also regulate lipid accumulation in the lipid-storing intestinal cells of C. elegans 34 , 35 . In mice, Lrig3 -deficient animals display altered plasma lipid levels 36 .…”

BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes in Caenorhabditis elegans

“…We tested the functions of putative target genes encoding DNA licensing factors and cyclins that could regulate polyploidization, but knockdown of these genes by RNAi did not produce body size phenotypes (Supplemental Material, Figure S1). We next analyzed the functions of target genes involved in fat metabolism, but discovered that they function independently of body size regulation (Clark et al 2018). Finally, we turned our attention to four cuticle collagen genes that we identified as putative transcriptional targets of the DBL-1 pathway.…”

Membrane Fluidity Is Regulated Cell Nonautonomously byCaenorhabditis elegansPAQR-2 and Its Mammalian Homolog AdipoR2

“…For example, the gonad is able to communicate to the intestine to regulate vitellogenin production ( Balklava et al 2016 ) whereas the intestine can regulate germline sex determination via specific signaling fatty acids ( Tang and Han 2017 ). Similarly, the hypodermis can modulate lipid accumulation in the intestine via a sma-3 dependent signal ( Clark et al 2018 ). This signaling hypothesis may explain why expression of paqr-2 and fat-6 did not rescue the fertility in the paqr-2 ; fat-6 double mutant: systemic paqr-2 -dependent membrane homeostasis from the gonad sheath cells may depend on a signal reaching fat-6 –expressing tissues such as the hypodermis or intestine.…”