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Int J Biol Sci,
2009]
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 Kruppel-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.
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Annu Rev Physiol,
2015]
Over the past decade, studies conducted in Caenorhabditis elegans have helped to uncover the ancient and complex origins of body fat regulation. This review highlights the powerful combination of genetics, pharmacology, and biochemistry used to study energy balance and the regulation of cellular fat metabolism in C. elegans. The complete wiring diagram of the C. elegans nervous system has been exploited to understand how the sensory nervous system regulates body fat and how food perception is coupled with the production of energy via fat metabolism. As a model organism, C. elegans also offers a unique opportunity to discover neuroendocrine factors that mediate direct communication between the nervous system and the metabolic tissues. The coming years are expected to reveal a wealth of information on the neuroendocrine control of body fat in C. elegans.
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Cell,
2003]
Drosophila geneticists have uncovered roles for microRNAs in the coordination of cell proliferation and cell death during development, and in stress resistance and fat metabolism. In C. elegans, a homolog of the well-known fly developmental regulator hunchbank acts downstream of the microRNAs
lin-4 and
let-7 in a pathway controlling
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Cell Metab,
2013]
Reduced reproduction is associated with increased fat storage and prolonged life span in multiple organisms, but the underlying regulatory mechanisms remain poorly understood. Recent studies in several species provide evidence that reproduction, fat metabolism, and longevity are directly coupled. For instance, germline removal in the nematode Caenorhabditis elegans promotes longevity in part by modulating lipid metabolism through effects on fatty acid desaturation, lipolysis, and autophagy. Here, we review these recent studies and discuss the mechanisms by which reproduction modulates fat metabolism and life span. Elucidating the relationship between these processes could contribute to our understanding of age-related diseases including metabolic disorders.
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WormBook,
2007]
As in all living organisms, survival in C. elegans requires adequate management of energy supplies. Genetic screens have revealed that C. elegans fat regulation involves a complex network of genes with known or likely functions in food sensation, neuroendocrine signaling, uptake, transport, storage and utilization of fats. Core fat and sugar metabolic pathways are conserved in C. elegans. Flux through these pathways is modulated by cellular energy sensors that operate via transcriptional and translational regulatory mechanisms. In turn, neuroendocrine mechanisms couple sensory and metabolic pathways while neuromodulatory pathways influence both metabolic and food seeking/consumption pathways. The shared ancestry of C. elegans and mammalian fat regulatory pathways extends to developmental programs that underlie fat storage capacity, despite lack of dedicated adipocytes, and genes whose human homologs are implicated in obesity. This suggests that many of the newly identified C. elegans fat regulatory pathways play similar roles in mammals. C. elegans is ideally suited for the integrated study of mechanisms that operate in multiple tissues and elicit feedback responses that affect processes as diverse as metabolism and behavior.
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Crit Rev Biochem Mol Biol,
2014]
C. elegans provides a genetically tractable system for deciphering the homeostatic mechanisms that underlie fat regulation in intact organisms. Here, we provide an overview of the recent advances in the C. elegans fat field with particular attention to studies of C. elegans lipid droplets, the complex links between lipases, autophagy, and lifespan, and analyses of key transcriptional regulatory mechanisms that coordinate lipid homeostasis. These studies demonstrate the ancient origins of mammalian and C. elegans fat regulatory pathways and highlight how C. elegans is being used to identify and analyze novel lipid pathways that are then shown to function similarly in mammals. Despite its many advantages, study of fat regulation in C. elegans is currently faced with a number of conceptual and methodological challenges. We critically evaluate some of the assumptions in the field and highlight issues that we believe should be taken into consideration when interpreting lipid content data in C. elegans.
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Bioessays,
2012]
New C. elegans studies imply that lipases and lipid desaturases can mediate signaling effects on aging. But why might fat homeostasis be critical to aging? Could problems with fat handling compromise health in nematodes as they do in mammals? The study of signaling pathways that control longevity could provide the key to one of the great unsolved mysteries of biology: the mechanism of aging. But as our view of the regulatory pathways that control aging grows ever clearer, the nature of aging itself has, if anything, grown more obscure. In particular, focused investigations of the oxidative damage theory have raised questions about an old assumption: that a fundamental cause of aging is accumulation of molecular damage. Could fat dyshomeostasis instead be critical?
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Trends Endocrinol Metab,
2009]
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.
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Curr Opin Cell Biol,
1999]
Cadherins are a superfamily of Ca(2+)-dependent adhesion molecules found in metazoans. Several classes of cadherins have been defined from which two - classic cadherins and Fat-like cadherins - have been studied by genetic approaches. Recent in vivo studies in Caenorhabditis elegans and Drosophila show that cadherins play an active role in a number of distinct morphogenetic processes. Classic cadherins function in epithelial polarization, epithelial sheet or tube fusion, cell migration, cell sorting, and axonal patterning. Fat-like cadherins are required for epithelial morphogenesis, proliferation control, and epithelial planar polarization.
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BioTechnologia (Pozn),
2021]
Obesity is a global health problem associated with many comorbidities such as type 2 diabetes and cancer. The number of individuals with overweight and obesity have increased dramatically within the past few years. Given the worldwide cost of an obesity pandemic, it is crucial to understand molecular pathways and identify novel factors that regulate fat storage in humans. In recent years, Caenorhabditis elegans has been widely used to investigate metabolic and neuroendocrine mechanisms involved in the regulation of energy metabolism. In this review, we describe similarities in fundamental signalling pathways regulating fat accumulation between nematodes and mammals. Like in humans, fat storage in C. elegans depends on the interaction of genetic and environmental factors such as diet, microbiota and ambient temperature. Despite many challenges, the simplicity of use, relatively short lifespan, genetic conservation and availability of many valuable experimental techniques make C. elegans an attractive and useful model organism in obesity research.