ARRA Investments in the Study of Brown Adipose Tissue
Public Health Burden
New research has revealed that an energy-burning form of fat is active in adults—a finding which may speed efforts to combat obesity. Unlike “white” fat, which stores energy and comprises most body fat, this other form of fat, called “brown adipose tissue” or “BAT,” burns calories to help keep animals warm. In humans, it has been thought that brown fat is active only in babies and children. However, three recent human studies support the idea that human adults have brown adipose tissue (it is not restricted to newborns) and it may not completely disappear during development to adulthood. The results from this work indicate that most if not all lean young and middle-aged adults have some cold-activated BAT, but it is less clear whether this tissue persists in elderly people or can be activated in the obese state. Most of the modern knowledge of brown adipose tissue is from studies in rodents, where BAT is known to generate heat in response to cold temperatures and activation of the autonomic nervous system. If this tissue is common in adult people, it could play a role in the metabolic response to the environment and could therefore be a determinant of differences in resting energy use, potentially predisposing people who live in a warm environment, or lack BAT, to obesity in a setting of abundant food. It may also be an important drug target for preventing or treating obesity. There are enormous difficulties associated with studying this tissue. Nevertheless, several studies have been proposed that will evaluate the contribution of BAT to overall energy expenditure.
Novel Technologies for Human BAT Detection
Although BAT is present in rodents throughout life, until recently BAT was thought to be nonexistent and metabolically irrelevant in adult humans. This was because, despite its potential physiological impact, there had been no methods to localize and quantify BAT mass and measure its activity or response to stimulation. However, based on newly reported findings, BAT is known to be present in most adult humans; it is functionally active and can be stimulated by physiological activators; and BAT mass and activity can be identified and quantified, by imaging methods. However, further investigations are needed in refining this imaging modality to quantify organ specific energy production, utilization, and heat production in human subjects. ARRA-funded grants are exploring ways of detecting BAT:
A study in rodents and humans to utilize complementary measures of whole-body energy expenditure and temperature will be correlated with findings using noninvasive imaging. These measures will be combined with physiological studies at the levels of the tissue and cell, as well as gene expression studies, which will provide a full picture of how BAT functions and exerts its beneficial effects on metabolism.
Mechanisms for BAT Activity
The observation that BAT can be identified now opens the field to increase the understanding of BAT metabolism. Despite this advance, further studies need to be conducted to determine specific mechanisms of energy production, utilization, and heat production of BAT. A variety of ARRA-funded grants are exploring this topic, including pilot studies designed for collecting data to inform larger trials:
A project to examine the biochemical pathways regulating the energy expenditure in BAT that help control energy balance along with pathways that may affect BAT gene expression profiles.
A study monitoring gene expression, as well as cellular function and morphology, to examine the development of BAT correlated with measurements of BAT heat generation in mice.
A study to investigate the key cellular regulators of fat tissue metabolism to control the mobilization of stored energy and adaptive heat generation in BAT.
BAT Gene Expression Profiles
Different fat depots within the body are not only distinct by anatomical location, but also are characterized by relatively unique gene expression. While considerable overlap exists with respect to genes that dictate mature fat cell function, is also clear that distinct fat depots express unique subsets of genes resulting in physiologically distinct adipose tissues. Some examples of ARRA-funded grants focused on this topic are:
A study to examine gene expression in BAT fat pads to determine whether BAT-specific gene expression involves distinct clusters or mostly individual genes.
A project conduced in the Rodent Gene Array Program (R-GAP) to create gene expression and genotype databases on a large panel of recombinant inbred rat strains across four tissues that manifest deleterious effects of alcoholism: heart, liver, gut, and BAT.
Neural Control of BAT Activity
Understanding the nerve pathways and mechanisms that inhibit neural signaling outflow to BAT will provide a foundation for determining how alterations in these pathways contribute to overweight and obesity. Such studies are an important step towards the development of therapeutic approaches to combat obesity by increasing energy expenditure even under conditions of dietary restriction. A number of ARRA-funded grants are exploring this topic:
A grant elucidating the neural pathway responsible for the decrease in nerve activation of BAT under certain physiological conditions.
A project to study the activity of certain types of neurons involved in body temperature regulation in response to histamine; changes in body temperature and energy expenditure induced by histamine; and how this system may be disrupted in a well-known obesity mouse model.
-- Imaging Strategies to Measure Brown Fat and Its Activity -- Kahn, C. Ronald (MA)
-- Characterization of TGR5-D2-WSB1 Signaling in Metabolic Homeostasis In Vivo -- Bicanco, Antonio C. (FL)
3R01DK048873-14S2 -- Regulation of Hepatic Lipid and Glucose Metabolism by Phosphatidylcholine Transferase -- Cohen, David E. (MA)
-- Beta-adrenergic Regulation of Adipose Tissue Function by PKA and MAP Kinases -- Collins, Sheila (NC)
-- Dissecting Adipose Depot-Selective Regulation of Gene Programs -- Scherer, Philipp E. (TX)
-- Gene Array Technology Center for Alcohol Research (The R-GAP) -- Tabakoff, Boris (CO)
-- Neural Circuitry Responsible for Metabolic Inhibition of Adaptive Thermogenesis -- Madden, Christopher J. (OR)
3R01NS060799-01A2S2 -- Preoptic histamine signaling in thermoregulation and energy expenditure -- Tabarean, Iustin Virgi (CA)
Page Last Updated on June 30, 2018
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