The MXL-3/SBP-1 Axis Is Responsible for Glucose-Dependent Fat Accumulation in C. elegans

Abstract

Chronic exposure to elevated glucose levels leads to fatty acid accumulation, which promotes the development of metabolic diseases such as obesity and type 2 diabetes. MXL-3 is a conserved transcriptional factor that modulates the inhibition of lipolysis in Caenorhabditis elegans. However, the role of MXL-3 in lipid metabolism during nutrient excess remains unknown. We hypothesized that inhibition of MXL-3 prevents glucose-dependent fat accumulation. Nematodes from wild-type N2, MXL-3::GFP and sbp-1 or mxl-3 null strains were grown on standard, high glucose or high glucose plus metformin plates for 24 h. Using laser-scanning confocal microscopy, we monitored the glucose-induced activation of MXL-3 labeled with GFP (MXL-3::GFP). Lipid levels were determined by Oil Red O (ORO) staining and gas chromatography/mass spectrometry, and gene expression was assessed by qRT-PCR. We found that high glucose activated MXL-3 by increasing its rate of nuclear entry, which in turn increased lipid levels via sterol regulatory element-binding protein (SBP-1). This activated critical genes that synthesize long chain unsaturated fatty acids (MUFAs and PUFAs) and repress lipolytic genes. Interestingly, the anti-diabetic drug metformin inhibited MXL-3 activation and subsequently prevented glucose-dependent fat accumulation. These findings highlight the importance of the MXL-3/SBP-1 axis in the regulation of lipid metabolism during nutritional excess and provide new insight into the mechanism by which metformin prevents lipid accumulation. This study also suggests that inhibition of MXL-3 may serve as a potential target for the treatment of chronic metabolic diseases, including obesity, type 2 diabetes, and cardiovascular disease.

Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling

“…SBP-1, the homolog of the mammalian sterol regulatory element-binding protein (SREBF2) transcription activator that regulates fatty acid homeostasis, is a known partner of MDT-15, and together, MDT-15 and SBP-1 promote the expression of lipid synthesis genes ( 32 ). FASN-1 encodes the sole C. elegans fatty acid synthase, and its expression is regulated by MDT-15/SBP-1 ( 38 , 39 ). Together, MDT-15, SBP-1, and FASN-1 may act to promote the synthesis of a lipid-based factor that signals for, or is otherwise required for, neuronal exopher production under fasting stress.…”

“…The requirement for mdt - 15 in fasting-induced, neuronal exophergenesis adds a new facet to the MDT-15 integration of multiple, transcriptional regulatory pathways ( 32 ), expanding the known roles of MDT-15/SBP-1 to include the activation of extrusion of remote neuronal aggregates in exophers. SBP-1/SREBF2 acts with MDT-15 to promote the expression of lipid metabolism genes ( 33 , 34 ), and fatty acid synthase fasn - 1 can be regulated by these ( 38 , 39 , 62 , 64 , 65 ). The requirement for multiple genes involved in lipid synthesis in fasting-induced exopher increase suggests that a lipid-based signal may be issued to ultimately direct or modulate neuronal trash expulsion.…”

A high glucose diet induces autophagy in a HLH-30/TFEB-dependent manner and impairs the normal lifespan of C. elegans

“…Nematodes of each experimental condition were collected in M9 (6 g Na 2 HPO 4 , 3 g KH 2 PO 4 , 5 g NaCl, 0.25 g MgSO 4 , in 1 L of H 2 O), washed 3 times and flash frozen in liquid nitrogen. Total RNA was extracted by the Proteinase K (Boehringer-Ingelheim) method and purified by TRIzol® as previously described [ 35 , 36 ]. RNA quantification was performed with a NanoDrop® at 260 nm.…”

Peripheral cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin synthesis

“…Glucose is an essential nutrient and the main component of metabolism and energy production. In C. elegans , like its action in mammals, dietary glucose supplementation increases fat accumulation [30, 31] and hence leads to some pathophysiological changes, such as accelerated aging and life shorting [32, 33]. Palmitic acid is one of the most common saturated fatty acids in the human body [34] and the primary saturated fatty acid in E. coli OP50 membrane [35].…”