Systems genetic analysis of brown adipose tissue function

Brown adipose tissue (BAT) has been suggested to play an important role in lipid and glucose metabolism in rodents and possibly also in humans. In the current study, we used genetic and correlation analyses in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), to identify genetic determinants of BAT function. Linkage analyses revealed a quantitative trait locus (QTL) associated with interscapular BAT mass on chromosome 4 and two closely linked QTLs associated with glucose oxidation and glucose incorporation into BAT lipids on chromosome 2. Using weighted gene coexpression network analysis (WGCNA) we identified 1,147 gene coexpression modules in the BAT from BXH/HXB rats and mapped their module eigengene QTLs. Through an unsupervised analysis, we identified modules related to BAT relative mass and function. The Coral4.1 coexpression module is associated with BAT relative mass (includes Cd36 highly connected gene), and the Darkseagreen coexpression module is associated with glucose incorporation into BAT lipids (includes Hiat1, Fmo5, and Sort1 highly connected transcripts). Because multiple statistical criteria were used to identify candidate modules, significance thresholds for individual tests were not adjusted for multiple comparisons across modules. In summary, a systems genetic analysis using genomic and quantitative transcriptomic and physiological information has produced confirmation of several known genetic factors and significant insight into novel genetic components functioning in BAT and possibly contributing to traits characteristic of the metabolic syndrome.

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Seasonal variations in the mass and composition of brown adipose tissue in the meadow vole, Microtus pennsylvanicus

Canadian Journal of Zoology ◽

10.1139/z69-096 ◽

1969 ◽

Vol 47 (4) ◽

pp. 547-555 ◽

Cited By ~ 19

Author(s):

L. A. Didow ◽

J. S. Hayward

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Seasonal Changes ◽

Microtus Pennsylvanicus ◽

Meadow Vole ◽

Relative Mass ◽

Laboratory Studies ◽

Meadow Voles ◽

Percentage Composition ◽

Brown Adipose

Wild meadow voles were collected each month of the year and analyzed for the mass and composition of their brown adipose tissue. The relative mass of brown adipose tissue decreased with increasing body weight in both summer and winter.Seasonal changes in the relative mass of brown adipose tissue were inversely related to seasonal changes in ambient temperature. In mature voles, the relative mass of brown adipose tissue was lowest during summer (0.5%) and increased rapidly to a level of 1.7% in early winter. Similarly, immature voles had their lowest relative mass in summer (1.0%) and increased this to 2.3% in winter. Both groups showed some decrease in the winter amount of the tissue when the subnivean environment became established. The percentage composition of brown adipose tissue with respect to water, lipid, and protein did not change significantly through the year.The results provide corroboration for laboratory studies which show that the mass and composition of brown adipose tissue are related to the requirement for cold thermogenesis. In voles, this requirement was present throughout the year and varied only in degree.

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Genetic background and diet affect brown adipose gene coexpression networks associated with metabolic phenotypes

Physiological Genomics ◽

10.1152/physiolgenomics.00003.2020 ◽

2020 ◽

Vol 52 (6) ◽

pp. 223-233 ◽

Cited By ~ 1

Author(s):

Caryn Carson ◽

Heather A. Lawson

Keyword(s):

Adipose Tissue ◽

Cell Division ◽

Brown Adipose Tissue ◽

Genetic Background ◽

Cytokine Response ◽

Transcriptional Networks ◽

Metabolic Phenotypes ◽

Gene Coexpression ◽

Obesity And Diabetes ◽

Brown Adipose

Adipose is a dynamic endocrine organ that is critical for regulating metabolism and is highly responsive to nutritional environment. Brown adipose tissue is an exciting potential therapeutic target; however, there are no systematic studies of gene-by-environment interactions affecting function of this organ. We leveraged a weighted gene coexpression network analysis to identify transcriptional networks in brown adipose tissue from LG/J and SM/J inbred mice fed high- or low-fat diets and correlate these networks with metabolic phenotypes. We identified eight primary gene network modules associated with variation in obesity and diabetes-related traits. Four modules were enriched for metabolically relevant processes such as immune and cytokine response, cell division, peroxisome functions, and organic molecule metabolic processes. The relative expression of genes in these modules is highly dependent on both genetic background and dietary environment. Genes in the immune/cytokine response and cell division modules are particularly highly expressed in high fat-fed SM/J mice, which show unique brown adipose-dependent remission of diabetes. The interconnectivity of genes in these modules is also heavily dependent on diet and strain, with most genes showing both higher expression and coexpression under the same context. We highlight several genes of interest, Col28a1, Cyp26b1, Bmp8b, and Ngef, that have distinct expression patterns among strain-by-diet contexts and fall under metabolic quantitative trait loci previously mapped in an F16 generation of an advanced intercross between LG/J and SM/J. Each of these genes have some connection to obesity and diabetes-related traits, but have not been studied in brown adipose tissue. Our results provide important insights into the relationship between brown adipose and systemic metabolism by being the first gene-by-environment study of brown adipose transcriptional networks.

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Mechanisms of stimulus-calorigenesis coupling in brown adipose tissue

Canadian Journal of Biochemistry and Cell Biology ◽

10.1139/o84-083 ◽

1984 ◽

Vol 62 (7) ◽

pp. 623-630 ◽

Cited By ~ 14

Author(s):

Ludwik J. Bukowiecki

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mitochondrial Respiration ◽

Uncoupling Protein ◽

Relative Mass ◽

Tissue Respiration ◽

Beta Oxidation ◽

Brown Adipose ◽

Hormone Sensitive

The sequence of metabolic events leading to increased calorigenesis in brown adipose tissue has been reviewed. The first step of this sequence consists in the binding of norepinephrine to adrenergic receptors of the beta1 subtype. This results in the stimulation of adenylate cyclase and activation of lipolysis via the system of protein kinases. Hormone-sensitive lipases represent the "flux-generating" step regulating mitochondrial respiration. Fatty acids released from intracellular triglyceride droplets in consequence of lipase activation play a messenger role between lipolysis and mitochondrial respiration. They stimulate respiration by serving as substrates for beta oxidation (via carnitine-dependent pathways) and (or) by simultaneously increasing mitochondrial permeability to protons (physiological "loose coupling"). The control of brown adipose tissue respiration by lipolysis represents a self-regulatory process, as excessive concentrations of fatty acids retroinhibit lipolysis. At the mitochondrial level, fatty acids appear to interact with an "uncoupling" protein (thermogenin or 32 000 relative mass protein) localized in the inner membrane that confers upon brown adipose mitochondria a unique sensitivity for fatty acid uncoupling. This explains that, contrary to other tissues, respiration is principally controlled in brown adipose tissue by substrate supply (mainly long-chain fatty acids), rather than by the phosphorylation state ratio.

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Altered effect of insulin and catecholamines in brown adipose tissue of cold-acclimated rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y79-049 ◽

1979 ◽

Vol 57 (3) ◽

pp. 320-324 ◽

Cited By ~ 4

Author(s):

Nicole Bégin-Heick ◽

Iris Noland ◽

Marthe Dalpé ◽

H. M. C. Heick

Keyword(s):

Adipose Tissue ◽

Plasma Membrane ◽

Adenylate Cyclase ◽

Brown Adipose Tissue ◽

Cold Acclimation ◽

Inhibitory Action ◽

Cyclase Activity ◽

Relative Response ◽

Brown Adipose ◽

Glucose Incorporation

Data are presented indicating that in brown adipose tissue (BAT) of cold-acclimated (CA), but not cold-exposed (CE) rats, there was an alteration in the relative response to catecholamines and insulin as evidenced by increased binding of alprenolol and decreased binding of insulin to plasma membrane enriched fractions. In addition, the stimulatory effect of insulin on glucose incorporation into glycogen and its inhibitory action on adenylate cyclase activity were both blunted in the CA tissues. It is proposed that shifts in the capacity of BAT to respond to catecholamines and insulin may be involved in the mechanism of cold acclimation.

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Functional characterization of human brown adipose tissue metabolism

Biochemical Journal ◽

10.1042/bcj20190464 ◽

2020 ◽

Vol 477 (7) ◽

pp. 1261-1286 ◽

Cited By ~ 3

Author(s):

Marie Anne Richard ◽

Hannah Pallubinsky ◽

Denis P. Blondin

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Functional Characterization ◽

Human Infants ◽

Positron Emission ◽

Brown Adipose ◽

Treatment Of Obesity ◽

And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

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