Midgut-Derived Activin Regulates Glucagon-like Action in the Fat Body and Glycemic Control.
While high-caloric diet impairs insulin response to cause hyperglycemia, whether and how counter-regulatory hormones are modulated by high-caloric diet is largely unknown. We find that enhanced response of Drosophila adipokinetic hormone (AKH, the glucagon homolog) in the fat body is essential for hyperglycemia associated with a chronic high-sugar diet. We show that the activin type I receptor Baboon (Babo) autonomously increases AKH signaling without affecting insulin signaling in the fat body via, at least, increase of Akh receptor (AkhR) expression. Further, we demonstrate that Activin-β (Actβ), an activin ligand predominantly produced in the enteroendocrine cells (EEs) of the midgut, is upregulated by chronic high-sugar diet and signals through Babo to promote AKH action in the fat body, leading to hyperglycemia. Importantly, activin signaling in mouse primary hepatocytes also increases glucagon response and glucagon-induced glucose production, indicating a conserved role for activin in enhancing AKH/glucagon signaling and glycemic control.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: rsong@genetics.med.harvard.edu.
Wei
W
Song
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China.
Daojun
D
Cheng
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Shangyu
S
Hong
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Benoit
B
Sappe
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Yanhui
Y
Hu
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Neil
N
Wei
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Changqi
C
Zhu
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Michael B
MB
O'Connor
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Pavlos
P
Pissios
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: perrimon@receptor.med.harvard.edu.
Norbert
N
Perrimon
D029404:Activin Receptors / Q000378:metabolism; D028341:Activins / Q000378:metabolism*; D000818:Animals; D050260:Carbohydrate Metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000378:metabolism; D005216:Fat Body / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D007301:Insect Hormones / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
C533337:AKHR protein, Drosophila; D002352:Carrier Proteins; C517156:Daw protein, Drosophila; D004040:Dietary Carbohydrates; D029721:Drosophila Proteins; D007301:Insect Hormones; D009842:Oligopeptides; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D028341:Activins; C065368:DAKH peptide; D005934:Glucagon; D029404:Activin Receptors; C517157:Babo protein, Drosophila; D011761:Pyrrolidonecarboxylic Acid