Nutrient Sensing: When You Hunger for More!

In step with the increasing numbers of patients with diabetes from caloric surfeit, there is great progress in understanding the complex interrelated mechanisms contributing to overeating. This highly interdisciplinary symposium brings together 6 outstanding scientists with disparate backgrounds and perspectives, yet with synergistic knowledge, contributing to our understanding of excessive caloric intake. Their expertise spans global energy balance to chemical recognition of caloric excess, incorporates breaking news of neural pathways from glial sensing to supermarket choices, and surveys our obesifying endogenous microbiota.

The Diabetes and Obesity discussion group explores the correlation between the growing trend of obesity and rising number of those diagnosed with diabetes.

Organizer: John G. Kral (SUNY Downstate Medical Center)

Speakers: James H. Brown, University of New Mexico; John A. Hanover, NIDDK, National Institutes of Health; Shai Shaham, The Rockefeller University; Ruth E. Ley, Cornell University; Gary J. Schwartz, Albert Einstein College of Medicine; Randy J. Seeley, University of Cincinnati

Abstracts

Working for Food
James H. Brown, University of New Mexico

Maintaining healthy weight and condition requires the right balance between food assimilation and metabolic expenditure. This is especially relevant for normal growth and development, which depend on regulating rates of assimilation, maintenance metabolism, and production of new biomass (storage). Careful measurements and manipulative experiments on growing mammals and birds provide empirical background to guide models of metabolic allocation. Of particular interest are experiments in which animals are reared on diets that provide either insufficient or excessive resources, potentially leading to either retarded development or obesity, respectively. After summarizing recent theoretical and empirical work on growth by Chen Hou and our "scaling group", I will speculate about more general problems of balancing supply and demand in metabolism: e.g., the fractal-like designs of circulatory, respiratory, digestive, and excretory systems; allometric scaling of cell size and metabolic rate in different cell types; and the role of angiogenesis in fueling the growth of cancer tumors.

Carbo-loading: Biochemistry of Nutrient excess and Famine
John A. Hanover, NIDDK, National Institutes of Health

The cellular response to feast or famine is mediated by the concerted action of a variety of key signaling pathways including the AMP-kinase, mTOR and Hexosamine-signaling pathways. In turn, these pathways interact with, and serve to modulate, homeostatic mechanisms such as the Insulin signaling, TGF-ß and MAP kinase signaling cascades. The Hexosamine-signaling pathway is of particular interest since it is responsive to cellular levels of amino acids, sugars and ATP. Growing evidence suggests that O-GlcNAc, the end product of the hexosamine-signaling pathway, modulates intracellular signaling by its covalent attachment to key components of kinase-dependent signaling cascades. The enzymes of O-GlcNAc cycling are recruited to their sites of action by the same activation mechanism (PI-3 kinase) triggering Insulin and many other signaling cascades. Thus, the Hexosamine-signaling pathway impacts Insulin signaling and other pathways by directly responding to nutrient availability. Our genetic evidence further suggests that Hexosamine-signaling by O-GlcNAc serves as an epigenetic modulator of transcription, translation, and protein stability. The two key enzymes in this process, O-GlcNAc transferase and O-GlcNAcase, have emerged as promising drug targets. The pathways impacted by the nutrient-responsive hexosamine-signaling pathway modulate key physiological processes dysregulated in metabolic syndrome (stress, innate immunity, and metabolism). In fact, the O-GlcNAcase gene is a known diabetes susceptibility locus in Mexican Americans. A 'vicious cycle' exists in such populations; children of mothers with diabetes show increased risk for developing the disease due to unknown epigenetic factors in the intrauterine environment. Our current hypothesis is that O-GlcNAc cycling integrates metabolic information, potentially leading to epigenetic reprogramming in the intrauterine environment.

Glia and Food Sensation
Shai Shaham, The Rockefeller University

Sensory organs are composed of neurons, which convert environmental stimuli to electrical signals, and glia-like cells, whose functions are not well-understood. To decipher glial roles in sensory organs, we ablated the sheath glial cell of the major sensory organ of Caenorhabditis elegans. We found that glia-ablated animals exhibit profound sensory deficits and that glia provide activities that affect neuronal morphology, behavior generation, and neuronal uptake of lipophilic dyes. To understand the molecular bases of these activities, we identified 298 genes whose mRNAs are glia enriched. One gene, fig-1, encodes a labile protein with conserved thrombospondin TSP1 domains. FIG-1 protein functions extracellularly, is essential for neuronal dye uptake, and also affects behavior. Our results suggest that glia are required for multiple aspects of sensory organ function, and suggest a broader role for these cells in the functions of nervous systems in general.

Feeding Gut Creatures
Ruth E. Ley, Cornell University

Humans, like other animals, are born germ-free. However, once born, we are rapidly colonized with microbial cells that outnumber our own eukaryotic cells 10 to 1. The largest assemblage of microbes resides in the gut, where densities can approach 1012 cells/mL. I will present recent research that has established a link between the composition of the gut microbial community and host energy balance. We have surveyed the populations of gut microbes inhabiting both lean and obese human and mouse hosts with high-throughput DNA sequencing approaches. These studies revealed that individuals acquire their resident microbes from their early environment, but that the relative abundances of the major groups of bacteria track host adiposity. The functional consequence of a shift in the proportion of the major bacterial groups is a greater capacity for energy harvest from the diet in the obese host. The role of diet, environment, host genotype and lifestyle come together to shape our inner microbial species, which in turn can impact our health.

Gut Feelings
Gary J. Schwartz, Albert Einstein College of Medicine

The proximal small intestine is a primary site for nutrient absorption during and between meals. Neural sensors in the gastrointestinal tract also relay information to brain sites in the hindbrain and forebrain important in limiting meal size. Intestinal lipid infusion elicits the local production of fatty acid derivatives that, in turn, promote satiety and reduce food intake. Intestinally infused lipids also rapidly suppress endogenous glucose production via a sensory vagal neural circuit linking the small intestine to the brainstem, which in turn modulates hepatic glucose production via the vagal motornueorns supplying the liver. This circuit provides an early warning system modulating endogenous glucose availability when nutrients are digested during or following a meal. These critical intestinal nutrient sensing areas are not stimulated after gastric bypass, which may account for the rapid and prolonged beneficial effects of this significant weight reduction therapy in treating type 2 diabetes and morbid obesity.

How Obesity Went to Our Heads
Randy J. Seeley, University of Cincinnati

Adult mammals, including humans, match their caloric intake to their caloric expenditure to maintain energy balance. To do so, the system must be able to monitor both the amount of stored fuel that in adipose tissue but also the amount of available fuel. Consequently, key regions of the hypothalamus must be sensitive to signals that convey information about both stored and available fuel. To monitor available fuel, the hypothalamus has adapted a number of fuel-sensing mechanisms used in peripheral cells. One of these is the atypical kinase mTOR. In hypothalamus, phosphorylated forms of mTOR are found exclusively in the arcuate and paraventricular nuclei and mTOR activity is reduced by fasting. Leucine is a powerful activator of mTOR activity and we found that CNS administration of low doses of leucine inhibit food intake in an mTOR-dependent manner. Further, leptin also increases hypothalamic mTOR and its anorexic actions depend on activating mTOR. Thus, mTOR signaling appears to be a metabolic regulator of food intake in the hypothalamus which integrates signals of available and stored fuel.