Abstract
Increasing brown adipose tissue (BAT) activity is regarded as a potential treatment of obese, hyperglycemic patients with metabolic syndrome. Triiodothyronine (T3) is known to stimulate BAT activity by increasing mitochondrial uncoupling protein 1 (Ucp1) gene transcription, leading to increased thermogenesis and decreased body weight. Here we report our studies on the effects of T3 and glucose in two mouse models and in mouse immortalized brown preadipocytes in culture. We identified carbohydrate response element binding protein (ChREBP) as a T3 target gene in BAT by RNA sequencing and studied its effects in brown adipocytes. We found that ChREBP was upregulated by T3 in BAT in both hyperglycemic mouse models. In brown preadipocytes, T3 and glucose synergistically and dose dependently upregulated Ucp1 messenger RNA 1000-fold compared with low glucose concentrations. Additionally, we observed increased ChREBP and Ucp1 protein 11.7- and 19.9-fold, respectively, along with concomitant induction of a hypermetabolic state. Moreover, downregulation of ChREBP inhibited T3 and glucose upregulation of Ucp1 100-fold, whereas overexpression of ChREBP upregulated Ucp1 5.2-fold. We conclude that T3 and glucose signaling pathways coordinately regulate the metabolic state of BAT and suggest that ChREBP is a target for therapeutic regulation of BAT activity.
Publication types
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Comparative Study
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Adipocytes, Brown / cytology
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Adipocytes, Brown / metabolism*
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Adipocytes, Brown / pathology
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Adipogenesis
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Cell Line, Transformed
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Cells, Cultured
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Diet, High-Fat / adverse effects
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Energy Metabolism
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Fatty Acid Synthase, Type I / chemistry
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Fatty Acid Synthase, Type I / genetics
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Fatty Acid Synthase, Type I / metabolism
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Gene Expression Profiling
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Gene Ontology
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Glucose Transporter Type 4 / agonists
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Glucose Transporter Type 4 / genetics
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Glucose Transporter Type 4 / metabolism
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Hyperglycemia / etiology
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Hyperglycemia / metabolism*
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Hyperglycemia / pathology
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Male
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Mice, Inbred C57BL
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Obesity / etiology
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Obesity / metabolism*
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Obesity / pathology
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Promoter Regions, Genetic
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RNA Interference
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Triiodothyronine / administration & dosage
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Triiodothyronine / metabolism*
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Uncoupling Protein 1 / agonists*
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Uncoupling Protein 1 / genetics
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Uncoupling Protein 1 / metabolism
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Up-Regulation*
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Glucose Transporter Type 4
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Mlxipl protein, mouse
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Nuclear Proteins
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Slc2a4 protein, mouse
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Transcription Factors
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Ucp1 protein, mouse
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Uncoupling Protein 1
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Triiodothyronine
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Fatty Acid Synthase, Type I