Neuronal control of intestinal lipid metabolism
It is known that regions within the brain can control metabolism, rate of energy expenditure and fat stores across the entire body. However, it is not fully clear how this is achieved. In addition to its potential practical value, addressing this problem would also help elucidate the broader principle of how complex neural circuits that integrate many inputs achieve selective control over different outputs in the body.
For gene- and pathway- discovery studies, we use the C. elegans model, with a particular focus towards discovering mechanisms by which central neurons regulate whole-body lipid metabolism. Major strengths of this model system include powerful molecular-genetic tools, screening capabilities that allow unbiased gene discovery, and ease of visualization of fluorescent reporters made amenable by a transparent body.
Thus far, our studies have defined a core neuronal circuit in the C. elegans nervous system that converts sensory information across distinct modalities, to regulate the rate and extent of metabolism in the intestine. We are finding that rather than functioning discretely, food-, oxygen- and pheromone-sensing neurons operate together to drive the conversion of fat to energy in the intestine. How is this sensory integration achieved? This question gets at the heart of circuit neuroscience, but with a twist: rather than behavior, we wish defining how neuronal and neuroendocrine circuits control internal physiological states.
A neuroendocrine peptide connects neuronal signals to intestinal lipid metabolism
Because the C. elegans intestinal cells are not directly innervated, any communication from the nervous system to the intestine must occur via endocrine mechanisms, that is, by molecules secreted from neurons that act upon the intestine in a non-cell-autonomous manner. In other words, how do the fat-regulatory neural circuits convey information to the rest of the animal?
To discover such molecules, we embarked on a genetic screen that led to the discovery of a conserved and secreted peptide called FLP-7, an ancestral tachykinin peptide. We found the receptor for the FLP-7/Tac peptide: it is the ortholog of the mammalian Neurokinin 2 Receptor, (NK2R), also called NPR-22 in C. elegans. The Tachykinin pathway defines the brain-to-gut axis that connects signals from the environment to the intestine to control the conversion of fats to energy.
In the intestine, the Tachykinin signal results in a sustained increase in the activity of a conserved enzyme called Adipocyte Triglyceride Lipase (ATGL) and mitochondrial beta-oxidation, the process by which stored fats are converted to usable energy. Few studies have explored the consequences of chronically increased mitochondrial activity. Using our system, we are interested in determining the long-term effects of sustained fat loss on organismal health and longevity.
Intestinal control of neuronal functions
If one fascinating feature of the brain is that it exerts integrated control over selective body functions, the other is that distal organs communicate back to the brain. Not only to relay their status, but perhaps also to alter brain functions and output.
While investigating the role of oxygen sensing neurons in stimulating fat loss in the intestine, we stumbled into an interesting observation: that the fat status of the intestine modulates the activity of the oxygen-sensing neurons themselves!
This feature of gut-to-neuron signaling can be directly visualized in living animals using genetically-encoded fluorescent sensors. Not only does fat status alter neuronal activity, but also affects behaviors on food, and alters the function of fat-regulatory neural circuits. In on-going studies and open projects, we are interested in discovering the molecular bases of interoception, or sensing of the internal state of the body.
A new genetic pathway for the control of lipid metabolism in mammals
Despite decades of research, the regulation of body weight in mammals is still incompletely understood. The ‘calories-in-calories-out’ theory of energy balance is not borne out by long-term studies, and what constitutes a good diet and for whom is still a matter of continuous debate. In addition, adiposity and longevity are not directly correlated humans or in other species.
Remarkably, critical elements of the C. elegans neuroendocrine fat regulatory circuit, discovered using unbiased screening-based approaches, are fully conserved in mammals. Genes of this pathway are enriched in relevant tissues including the hypothalamus, gut and adipose. Of note, some of the genes in this pathway show ancestry- and disease-specific polymorphisms in humans. The functional significance of these polymorphisms remains unclear. In new studies, we are exploring the potential significance of this pathway in mice and in human cells.