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OVERVIEW

To maintain adequate energy reservoirs in the context of a dynamic environment, animals have evolved sophisticated energy sensing mechanisms as well as behavioral, physiological, and metabolic responses that function in the maintenance of energy homeostasis in face of changing energetic supplies and demands. Thus understanding energy balance in the context of intact organisms requires an integrated, system-wide view of animal behavior, physiology, and metabolism. Aberrations in energy balance are associated with numerous pathological conditions ranging from type 2 diabetes, cardiovascular disease, and hypertension to cancer and even neurodegenerative disorders. Moreover, aging and metabolism are tightly intertwined. Thus, studying energy balance incorporates questions related to cellular and organismal energy sensing mechanism, communication between organ systems, how the nervous system processes information, and how aberrations in these processes underlie various diseases.

We use of C.elegans as a simplified and genetically tractable platform for identifying the molecular components of and disentangling the logic of complex homeostatic networks that underlie energy balance. The amenability of C.elegans to genetic and genomic analyses is unmatched in ease and feasibility compared to other multicellular experimental organisms and the relative simplicity of its nervous system offers the opportunity for functional dissection of neural basis of food-evoked responses. Because of the deep evolutionary origins of fat and feeding pathways, we believe that findings in C.elegans are broadly informative.

1. Analyses of neural fat and feeding regulatory circuits.
One of our most striking findings to date is identification of central energy regulatory circuits in C.elegans. Some of the neurally expressed genes that regulate C.elegans feeding are counterparts of genes whose mammalian, including the human counterparts, are central nervous system regulators of fat and feeding. Examples include the oxytocin signaling cascade and the transcription factor single-minded-1, which in humans is required for proper formation of a key region of the hypothalamus and mutations in which cause obesity.

To understand the overall logic of how the nervous system regulates energy balance, we have focused on neural serotonergic and TGF-β circuits. Each pathway serves as a sensory gauge of environmental conditions to simultaneously modulate food intake and foraging behaviors, fat content, growth, mating, and reproductive rate. In each case, changes in food availability modulate initiation of signaling from defined and very discreet sets of neurons. Receptors for these signals, however, are widely distributed. By functionally identifying the cellular sites of action and molecular mechanisms through which each signaling cascade modulates the wide range of behavioral and metabolic outputs, we reached the surprising conclusion that each signaling cascade regulates fat independent of its regulation of feeding behavior and other parameters. Thus, fat is not merely a consequence of feeding behavior; instead, neural perception of energy availability initiates a signaling cascade that determines whether energetic resources are directed toward build-up of fat reservoirs or are actively metabolized. These findings challenge some of the existing paradigms in fat regulation.

2. Metabolism and behavioral plasticity.
C.elegans as in mammals, exhibit food-modulated behavioral plasticity. For instance, following fasting, C.elegans temporary over-eat once they have been re-exposed to food. We recently discovered that specific metabolites of the tryptophan degradation pathway serve as indicators of energy status to modulate this and other food-related behaviors of C.elegans. Considering that tryptophan is an essential amino acid and that various metabolites of the tryptophan degradation pathway act as signaling molecules, we believe that this pathway is an ancient mechanism through which metabolism is translated into neural and other functions. Our preliminary data already link this pathway to ancient forms of learning and memory and immune function.

3. Analysis of cellular fuel gauge mechanisms and C.elegans counterparts of human obesity genes.
We are analyzing key metabolic fuel gauge pathways such as the TOR kinase and AMP-activated kinase, which link cellular metabolic pathways to growth and differential pathways. Additionally, we are investigating C.elegans counterparts of human obesity genes. Our general strategy is to first define regulatory relationships for each pathway through suppressor/enhancer genetics and then understand these relationships through subsequent cell biological and biochemical pathways. For instance, we recently demonstrated that, in C.elegans as humans, mutations in Bardet-Biedl syndrome (bbs) genes, cause fat accumulation. As the complex of BBS proteins is required for proper formation and functioning of cilia, cellular organelles enriched in signaling molecules, it is widely assumed that obesity of bbs mutants must be due to inappropriate localization of receptors with roles in body weight regulation. By analyzing the C.elegans bbs mutants, we discovered that while these mutants indeed have ciliary defects, the excess fat of these animals derives from excess secretion of dense-core vesicles rather than inappropriate signal receptor by cilia-localized receptors.

4. The role of environmentally pervasive pollutants in the rise of obesity.
Although different genetic backgrounds predispose individuals to obesity, its dramatic rise over the past few decades points to environmental and behavioral factors. As such, the recent increase in obesity has generally been attributed to increased caloric intake and sedentary lifestyles in the context of genetic predispositions. However, there is increasing evidence that a number of chemicals pervasive in the environment can act as endocrine disruptors to favor fat storage. Just as certain chemicals pervasive in our environment act endocrine disruptors with adverse effects on reproduction or development, epidemiological studies and animal experiments already show a link between exposure to environmental chemicals and obesity. A formidable challenge has been identifying the molecular mechanisms of their actions vis-a-vis obesity. The experimental challenges in this area are further complicated by the fact that obesogenic consequences of these compounds may be due to low dose combinatorial effects or due to epigenetic programs. This lack of molecular clarity has marginalized consideration of these agents as key drivers of obesity. To address this issue, we are using C.elegans both to screen for environmentally pervasive compounds that can act as fat increasing drugs and use worms to decipher their mechanisms of action.

5. Identification and analyses of molecular mechanisms of action of fat altering drugs.
The current paradigm of biomedical research is largely centered on identification of molecular targets followed by development of small molecules with which to modulate such targets. This strategy largely misses out on the rich potential of pharmacology to help drive discovery of biological processes. Furthermore, this prevailing paradigm rests on the assumption that phenotypes caused by specific genetic perturbations can be effectively mimicked by small molecules designed to act on the same molecular targets; an assumption that is frequently untenable. Finally, to understand drug action in the context of whole organisms, it is insufficient to simply know a given compound's targets. This is because rather than a set of discreet targets, biological organisms are intact, homeostatic systems perturbations to which can best be understood at a system-wide level.

We have leveraged the experimental advantage of C.elegans to screen through compound libraries to identify those that alter C.elegans fat. In collaborative efforts with laboratories of Dr. Shoichet (UCSF, QB3) and Dr. Roth (UNC-Chapel Hill), we have begun efforts aimed at understanding the mechanisms of actions of these compounds in the context of whole animals by combining in silico predictions with in vitro and in vivo validation of these predictions on C.elegans and mammalian pathways. Thus far, our findings support the notion that whole animal C.elegans screening can lead to identification of novel compounds that act on evolutionary conserved fat regulatory pathways and that these compounds, in turn, facilitate understanding the cellular and molecular circuits that underlie mechanisms of actions of these compounds. Some of these compounds can serve as easily portable experimental reagents with which to probe the complex relationship of metabolic pathways to a variety of physiological and pathophysiological processes in various experimental systems.