Krüppel-like family of transcription factors: an emerging new frontier in fat biology

Abstract

In mammals, adipose tissue stores energy in the form of fat. The ability to regulate fat storage is essential for the growth, development and reproduction of most animals, thus any abnormalities caused by excess fat accumulation can result in pathological conditions which are linked to several interrelated diseases, such as cardiovascular diseases, diabetes, and obesity. In recent years significant effort has been applied to understand basic mechanism of fat accumulation in mammalian system. Work in mouse has shown that the family of Krüppel-like factors (KLFs), a conserved and important class of transcription factors, regulates adipocyte differentiation in mammals. However, how fat storage is coordinated in response to positive and negative feedback signals is still poorly understood. To address mechanisms underlying fat storage we have studied two Caenorhabditis elegans KLFs and demonstrate that both worm klfs are key regulators of fat metabolism in C. elegans. These results provide the first in vivo evidence supporting essential regulatory roles for KLFs in fat metabolism in C. elegans and shed light on the human counterpart in disease-gene association. This finding allows us to pursue a more comprehensive approach to understand fat biology and provides an opportunity to learn about the cascade of events that regulate KLF activation, repression and interaction with other factors in exerting its biological function at an organismal level. In this review, we provide an overview of the most current information on the key regulatory components in fat biology, synthesize the diverse literature, pose new questions, and propose a new model organism for understanding fat biology using KLFs as the central theme.

Caenorhabditis elegans as a model for obesity research

“…They bind to the DNA CCAAT gene sequence (C/EBPs) areas where the binding of PPARs and proteins is located. 49 Located in the endoplasmic reticulum and regulated by insulin and glucagon, SREBPs govern lipid synthesis in humans. Insulin causes increased transcription of SREBP-1, which binds to its own promoter and initiates a feed-forward amplification of the transcriptional response.…”

Increased adipocyte differentiation may be mediated by extracellular calcium levels through effects on calreticulin and peroxisome proliferator activated receptor gamma expression in intramuscular stromal vascular cells isolated from Hanwoo beef cattle

“…The current model for adipocytes differentiation suggests that the entire differentiation process involves both PPARc and CEBP/a. CEBP/a is known to induce PPARc which in turn heterodimerizes with another nuclear receptor thus regulating the adipogenic program in favour of fat cell differentiation (Brey et al 2009). What occurs afterwards is a positive feedback loop between PPARc and CEBP/a that maintains the differentiated state (Wu et al 1999).…”

Inferring transcriptional regulators for sets of co-expressed genes by multi-objective evolutionary optimization

“…Among the most frequent TFs are Kruppel-like factors (e.g., KLF4 and KLF11), as well as forkhead transcription factors (e.g., FOXD3, FOXO3). KLFs have previously been published in the context of statins [34], [35] and were recently found to be involved in the adipogenesis pathway [30], [36]. The hypoxia inducible factor 1 (HIF1A) was previously found to be involved in the regulation of the ATP-binding cassette (ABCA1) and plays a role in hypoxia mediated inhibition of cholesterol synthesis [37], [38].…”