Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival.
The regulation of pancreatic β cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of β cell function, including regulation of β cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of β cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote β cell expansion by direct and indirect mechanisms. Free Fatty Acid Receptor 2 (FFA2) is a β cell-expressed GPCR that is activated by short chain fatty acids, particularly acetate. Recent studies of FFA2 suggest that it may act as a regulator of β cell function. Here, we set out to explore what role FFA2 may play in regulation of β cell mass. Interestingly, Ffar2(-/-) mice exhibit diminished β cell mass at birth and throughout adulthood, and increased β cell death at adolescent time points, suggesting a role for FFA2 in establishment and maintenance of β cell mass. Additionally, activation of FFA2 with Gαq/11-biased agonists substantially increased β cell proliferation in in vitro and ex vivo proliferation assays. Collectively, these data suggest that FFA2 may be a novel therapeutic target to stimulate β cell growth and proliferation.
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Stephanie R
SR
Villa
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Medha
M
Priyadarshini
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Miles H
MH
Fuller
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Tanya
T
Bhardwaj
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Michael R
MR
Brodsky
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Anthony R
AR
Angueira
Vanderbilt University, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Nashville, TN, USA.
Rockann E
RE
Mosser
Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, TN, USA.
Bethany A
BA
Carboneau
Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Sarah A
SA
Tersey
Multispan Inc., Hayward, CA, USA.
Helena
H
Mancebo
Midwestern University Department of Pharmaceutical Sciences, Downers Grove, IL, USA.
Annette
A
Gilchrist
Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medicine, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA.
Raghavendra G
RG
Mirmira
Vanderbilt University, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Nashville, TN, USA.|Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, TN, USA.|Tennessee Valley Health Authority, Department of Veterans Affairs, Nashville, TN, USA.
Maureen
M
Gannon
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
Brian T
BT
Layden
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005232:Fatty Acids, Volatile / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D043562:Receptors, G-Protein-Coupled
D005230:Fatty Acids, Nonesterified; D005232:Fatty Acids, Volatile; D011956:Receptors, Cell Surface; C506481:Ffar2 protein, mouse; D043562:Receptors, G-Protein-Coupled