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.
Highlights
Hyperglycemia is a key risk factor for the development of diabetes mellitus and metabolic syndrome
We determined whether lipid accumulation due to a high-glucose diet induced lipid accumulation in N2 animals, as demonstrated by an increase in the intensity of Oil Red O (ORO)
When we analyzed free fatty acids (FFA) grouped in families according to their saturation levels, we showed that the absence of the MXL-3 transcription factor decreased SFAs and poly-unsaturated fatty acids (PUFAs) but did not change mono-unsaturated fatty acids (MUFAs)
Summary
Hyperglycemia is a key risk factor for the development of diabetes mellitus and metabolic syndrome. Nowadays, both diseases have a substantial impact on public health and safety because. Genes 2017, 8, 307 they exacerbate the burden on health services [1,2]. These metabolic diseases result from an imbalance between the amounts of energy ingested and consumed and they are characterized by lipid dysregulation that affects energy homeostasis. The discovery and modulation of regulatory elements, such as transcriptional factors, represents a strategy for combating pernicious effects of diabetes and other complications of the metabolic syndrome
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