Adiponectin lowers glucose production by increasing SOGA.
Adiponectin is a hormone that lowers glucose production by increasing liver insulin sensitivity. Insulin blocks the generation of biochemical intermediates for glucose production by inhibiting autophagy. However, autophagy is stimulated by an essential mediator of adiponectin action, AMPK. This deadlock led to our hypothesis that adiponectin inhibits autophagy through a novel mediator. Mass spectrometry revealed a novel protein that we call suppressor of glucose by autophagy (SOGA) in adiponectin-treated hepatoma cells. Adiponectin increased SOGA in hepatocytes, and siRNA knockdown of SOGA blocked adiponectin inhibition of glucose production. Furthermore, knockdown of SOGA increased late autophagosome and lysosome staining and the secretion of valine, an amino acid that cannot be synthesized or metabolized by liver cells, suggesting that SOGA inhibits autophagy. SOGA decreased in response to AICAR, an activator of AMPK, and LY294002, an inhibitor of the insulin signaling intermediate, PI3K. AICAR reduction of SOGA was blocked by adiponectin; however, adiponectin did not increase SOGA during PI3K inhibition, suggesting that adiponectin increases SOGA through the insulin signaling pathway. SOGA contains an internal signal peptide that enables the secretion of a circulating fragment of SOGA, providing a surrogate marker for intracellular SOGA levels. Circulating SOGA increased in parallel with adiponectin and insulin activity in both humans and mice. These results suggest that adiponectin-mediated increases in SOGA contribute to the inhibition of glucose production.
Cowherd
Rachael B
RB
Departments of Nutrition, School of Medicine and Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Cowerd
Rachael B
RB
Asmar
Melissa M
MM
Alderman
J McKee
JM
Alderman
Elizabeth A
EA
Garland
Alaina L
AL
Busby
Walker H
WH
Bodnar
Wanda M
WM
Rusyn
Ivan
I
Medoff
Benjamin D
BD
Tisch
Roland
R
Mayer-Davis
Elizabeth
E
Swenberg
James A
JA
Zeisel
Steven H
SH
Combs
Terry P
TP
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000097:blood* / Q000494:pharmacology*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001786:Blood Glucose / Q000378:metabolism*; D003001:Cloning, Molecular; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood*; D007328:Insulin / Q000097:blood*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D011817:Rabbits; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D055815:Young Adult
D052242:Adiponectin; D000071183:Autophagy-Related Proteins; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C000602895:SOGA1 protein, human; C556442:suppressor of glucose by autophagy protein, mouse; D055372:AMP-Activated Protein Kinases
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