Kaveh Ashrafi, PhD

Jack and DeLoris Lange Assistant Professor of Systems Physiology
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Regulation of fat content involves a complex interplay between central regulators of feeding behavior in the nervous system, neuroendocrine signals, and metabolic regulators of energy expenditure and fat storage.   We use genetic, cellular, and molecular approaches for understanding the networks that underlie the regulation of body fat in C. elegans.  By combining classical mutagenesis screens with RNA-mediated interference to disrupt the expression of thousands of individual worm genes, we have identified over 500 genes that, when inactivated, affect body fat content.  These fat regulatory genes include receptors, channels, signal transduction molecules, transcription and translation factors, vesicular transporters, metabolic enzymes, and a number of genes with unassigned functions.  The shared ancestry of the known mammalian and worm fat regulatory genes suggest that many of these newly identified genes may also function in human fat regulation.

Our goals are i) to understand the molecular functions and modes of
regulation of the newly identified genes, ii) to understand the principles that govern how hundreds of genes whose products are expressed in multiple tissues network to regulate a complex physiological process, iii) to delineate the neuronal networks that regulate food intake and energy expenditure, and iv) to extend these findings to identify mammalian fat and obesity genes and analyze disease associated genes.
To decipher the modes of function of the newly identified genes, we are establishing genetic interaction networks between various mutants and RNAi clones that cause fat reduction or fat increase. We take advantage of suppressor/enhancer screens to disentangle the complex feedback loops that affect body fat.

Fat regulatory genes can be broadly classified as those that impact food intake or energy expenditure.  Thus, we measure each of these parameters in the mutant animals or animals exposed to each fat regulatory RNAi clone.

