Artificial sweeteners stimulate adipogenesis and suppress lipolysis independently of sweet taste receptors.
G protein-coupled receptors mediate responses to a myriad of ligands, some of which regulate adipocyte differentiation and metabolism. The sweet taste receptors T1R2 and T1R3 are G protein-coupled receptors that function as carbohydrate sensors in taste buds, gut, and pancreas. Here we report that sweet taste receptors T1R2 and T1R3 are expressed throughout adipogenesis and in adipose tissues. Treatment of mouse and human precursor cells with artificial sweeteners, saccharin and acesulfame potassium, enhanced adipogenesis. Saccharin treatment of 3T3-L1 cells and primary mesenchymal stem cells rapidly stimulated phosphorylation of Akt and downstream targets with functions in adipogenesis such as cAMP-response element-binding protein and FOXO1; however, increased expression of peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α was not observed until relatively late in differentiation. Saccharin-stimulated Akt phosphorylation at Thr-308 occurred within 5 min, was phosphatidylinositol 3-kinase-dependent, and occurred in the presence of high concentrations of insulin and dexamethasone; phosphorylation of Ser-473 occurred more gradually. Surprisingly, neither saccharin-stimulated adipogenesis nor Thr-308 phosphorylation was dependent on expression of T1R2 and/or T1R3, although Ser-473 phosphorylation was impaired in T1R2/T1R3 double knock-out precursors. In mature adipocytes, artificial sweetener treatment suppressed lipolysis even in the presence of forskolin, and lipolytic responses were correlated with phosphorylation of hormone-sensitive lipase. Suppression of lipolysis by saccharin in adipocytes was also independent of T1R2 and T1R3. These results suggest that some artificial sweeteners have previously uncharacterized metabolic effects on adipocyte differentiation and metabolism and that effects of artificial sweeteners on adipose tissue biology may be largely independent of the classical sweet taste receptors, T1R2 and T1R3.
From the Program in Cellular and Molecular Biology.
Becky R
BR
Simon
Departments of Molecular and Integrative Physiology.
Sebastian D
SD
Parlee
Departments of Molecular and Integrative Physiology.
Brian S
BS
Learman
Departments of Molecular and Integrative Physiology.
Hiroyuki
H
Mori
Departments of Molecular and Integrative Physiology.
Erica L
EL
Scheller
Departments of Molecular and Integrative Physiology,; Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana 46285.
William P
WP
Cawthorn
Departments of Molecular and Integrative Physiology.
Xiaomin
X
Ning
Departments of Surgery.
Katherine
K
Gallagher
Cardiovascular and Metabolic Disease, MedImmune LLC, Gaithersburg Headquarters, Gaithersburg, Maryland 20878,; Metabolic Signaling and Disease, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827.
Björn
B
Tyrberg
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.
Fariba M
FM
Assadi-Porter
Departments of Molecular and Integrative Physiology.
Charles R
CR
Evans
From the Program in Cellular and Molecular Biology; Departments of Molecular and Integrative Physiology,; Internal Medicine, University of Michigan, Ann Arbor, Michigan 48105,. Electronic address: macdouga@umich.edu.
Ormond A
OA
MacDougald
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008066:Lipolysis / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012439:Saccharin / Q000494:pharmacology*; D013234:Stem Cells / Q000378:metabolism*; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism; D013549:Sweetening Agents / Q000009:adverse effects* / Q000493:pharmacokinetics
D000276:Adjuvants, Immunologic; D022763:CCAAT-Enhancer-Binding Protein-alpha; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; D013549:Sweetening Agents; C431926:taste receptors, type 1; D005576:Colforsin; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002787:Sterol Esterase; D012439:Saccharin
Acesulfame K; Adipogenesis; Akt; G Protein-coupled Receptors (GPCR); Lipolysis; Metabolism; Saccharin; T1R2; T1R3