Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Oct;177(4):1936-45.
doi: 10.2353/ajpath.2010.100363. Epub 2010 Sep 2.

Adiponectin lowers glucose production by increasing SOGA

Rachael B Cowherd  1 , Melissa M Asmar, J McKee Alderman, Elizabeth A Alderman, Alaina L Garland, Walker H Busby, Wanda M Bodnar, Ivan Rusyn, Benjamin D Medoff, Roland Tisch, Elizabeth Mayer-Davis, James A Swenberg, Steven H Zeisel, Terry P Combs
Affiliations

Adiponectin lowers glucose production by increasing SOGA

Rachael B Cowherd et al. Am J Pathol. 2010 Oct.

Erratum in

  • Am J Pathol. 2011 Mar;178(3):1406. Cowerd, Rachael B [corrected to Cowherd, Rachael B]

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Predicted functional domains of SOGA. A: SOGA map showing the location of conserved ATG16 and Rab5-binding motifs, the signal peptide, and the species-specific epitope in the predicted 161-kDa SOGA. The map also shows the predicted domains of the 80-kDa peptide detected in liver, hepatocytes, and hepatocyte-conditioned media and the 25–kDa peptide detected in plasma. B: The amino acid sequence for murine SOGA showing the location of the Atg16 (232–375) and Rab5-binding (757–886) motifs underlined, the signal peptide (593–614) in bold, the tryptic peptide identified by mass spectrometry (703–718) shaded, and the species specific domain (1392–1416) in a box. The position of the internal signal peptide explains why our antibodies, recognizing the species-specific epitope near the C terminus of SOGA, detect an 80-kDa SOGA peptide rather than the 161-kDa SOGA protein.
Figure 2
Figure 2
Function and regulation of SOGA in primary hepatocytes. A: Representative SDS-PAGE of primary murine hepatocyte samples showing the knockdown of 80-kDa SOGA as a function of time after exposure to siRNA. B: Representative purified binucleate hepatocyte cultures transfected with control (left) or SOGA siRNA (right) stained with the late autophagosome and lysosome-specific fluorescent dye LysoTracker Red. Control siRNA-transfected cultures exhibited an average of two isolated punctate stained vacuoles per hepatocyte (indicated by green arrows), whereas SOGA siRNA-transfected cultures showed an average of 18 stained vacuoles per hepatocyte. C: Bar graphs showing the effects of adiponectin and SOGA siRNA on glucose and valine in hepatocyte conditioned media (top and middle) and 80-kDa SOGA in hepatocytes (bottom). Densitometry was used to determine the ECL (enhanced chemiluminescent) signal after SDS-PAGE. D: Bar graphs showing the roles of AMPK and PI3K on adiponectin regulation of intracellular and extracellular SOGA levels. Primary hepatocytes were incubated in the presence or absence of the 500 μmol/L AICAR, a stimulator of AMPK, or 10 nmol/L LY294002, a PI3K inhibitor. Bars represent mean values ± SEM for n = 4 per group where there is a significant a difference compared with control (left bar) at *P < 0.05 by nonparametric Student's t-test. Gray and black bars indicate whether measurements were made in hepatocyte conditioned media or hepatocytes, respectively. ND indicates not detected.
Figure 3
Figure 3
Circulating adiponectin and SOGA levels in humans and mice. A: Adiponectin and 25-kDa SOGA levels in human plasma from healthy female volunteers (ages 20–63; n = 13). Plasma was collected after an overnight fast. Values represent averages from two plasma samples taken 10 minutes apart. A correlation coefficient (R2) of 0.82 was found between SOGA and adiponectin. B: The effect of AL versus 30% CR feeding on adiponectin, SOGA, and glucose in female wild-type mice. Bar graphs show levels of plasma adiponectin (top), 25-kDa SOGA (middle), and glucose (bottom). C: The effect of pioglitazone treatment on liver SOGA mRNA and circulating adiponectin, SOGA, and glucose in diabetic ob/ob mice. Mice received a daily dose of pioglitazone (TZD) or placebo (CTL) by oral gavage. Bar graphs show the levels of plasma adiponectin (top), liver SOGA mRNA/18S RNA (second), plasma 25 kDa SOGA (third), and plasma glucose (bottom) after 4 days of treatment. D: Circulating levels of adiponectin and SOGA in male adiponectin transgenic mice and their wild-type littermates on a high-fat diet. Bars in panels B, C, and D represent mean ± SEM for n = 4–5 per group where there is a significant difference (*P < 0.05) by nonparametric Student's t-test.
Figure 4
Figure 4
Circulating levels of SOGA in relation to insulin in humans and mice. A: Percent change in circulating levels of SOGA in healthy human volunteers (20–43 years old) measured at 8:00–11:00 AM, either at two hours after feeding or following an overnight (10–12 hour) fast. Bars represent mean values ± SEM for n = 5, and there is a significant a difference at *P < 0.05 by nonparametric Student's t-test. B: The effect of insulin withdrawal and insulin injection on SOGA and glucose in female NOD mice. Circulating levels of 25-kDa SOGA and glucose in NOD mice without diabetes (Group 1), NOD mice with diabetes (Group 2), and NOD mice with diabetes treated by a single injection of insulin 24 hours earlier (Group 3). Bar graphs show the levels of plasma SOGA (top) and glucose (bottom). Bars show mean ± SEM for n = 5 per group. Statistical significance was determined by Student's t-test where *P < 0.05.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Goldfine AB, Kahn CR. Adiponectin: linking the fat cell to insulin sensitivity. Lancet. 2003;362:1431–1432. - PubMed
    1. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79–83. - PubMed
    1. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000;20:1595–1599. - PubMed
    1. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094–2099. - PubMed
    1. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930–1935. - PubMed

Publication types

MeSH terms

Associated data