Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo

Nature Communications

Volumn 6, Issue , 2015, Pages

  Titchenell, Paul M ^a   Chu, Qingwei ^a   Monks, Bobby R ^a   Birnbaum, Morris J ^a,b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOSE; INSULIN; INSULIN RECEPTOR; TRANSCRIPTION FACTOR FKHR; FORKHEAD TRANSCRIPTION FACTOR; FOXO1 PROTEIN, MOUSE; MESSENGER RNA;

GENE EXPRESSION; GENETIC ANALYSIS; GLUCOSE; HORMONE; INHIBITION; METABOLISM;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; GENE EXPRESSION; GLUCONEOGENESIS; GLUCOSE INTOLERANCE; GLUCOSE TOLERANCE; IN VITRO STUDY; IN VIVO STUDY; INSULIN RESISTANCE; INSULIN RESPONSE; MOUSE; NONHUMAN; SIGNAL TRANSDUCTION; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; GLUCOSE TOLERANCE TEST; KNOCKOUT MOUSE; LIVER; MALE; METABOLISM; PHYSIOLOGY;

ANIMALS; FORKHEAD BOX PROTEIN O1; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION; GLUCONEOGENESIS; GLUCOSE; GLUCOSE TOLERANCE TEST; INSULIN RESISTANCE; LIVER; MALE; MICE; MICE, KNOCKOUT; RECEPTOR, INSULIN; RNA, MESSENGER; SIGNAL TRANSDUCTION;

EID: 84929148324     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms8078     Document Type: Article

References (42)

1. Rizza, R. A. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. Diabetes 59, 2697-2707 (2010).
2. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799-806 (2001).
3. Lin, H. V. & Accili, D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab. 14, 9-19 (2011).
4. Leavens, K. F. & Birnbaum, M. J. Insulin signaling to hepatic lipid metabolism in health and disease. Crit. Rev. Biochem. Mol. Biol. 46, 200-215 (2011).
5. Menon, S. et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771-785 (2014).
6. Wan, M. et al. A noncanonical, GSK3-independent pathway controls postprandial hepatic glycogen deposition. Cell Metab. 18, 99-105 (2013).
7. Li, S., Brown, M. S. & Goldstein, J. L. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc. Natl Acad. Sci. USA 107, 3441-3446 (2010).
8. Wan, M. et al. Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. Cell Metab. 14, 516-527 (2011).
9. Nakae, J., Park, B. C. & Accili, D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmanninsensitive pathway. J Biol Chem 274, 15982-15985 (1999).
10. Rena, G. et al. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J. 21, 2263-2271 (2002).
11. Matsumoto, M., Pocai, A., Rossetti, L., Depinho, R. A. & Accili, D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab. 6, 208-216 (2007).
12. Dentin, R. et al. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449, 366-369 (2007).
13. Koo, S. H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109-1111 (2005).
14. Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423, 550-555 (2003).
15. Dong, X. C. et al. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 8, 65-76 (2008).
16. Samuel, V. T. et al. Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes 55, 2042-2050 (2006).
17. Lu, M. et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat. Med. 18, 388-395 (2012).
18. Michael, M. D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87-97 (2000).
19. Cheng, Z. & White, M. F. The AKTion in non-canonical insulin signaling. Nat. Med. 18, 351-353 (2012).
20. Haas, J. T. et al. Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression. Cell Metab. 15, 873-884 (2012).
21. Levine, R. & Fritz, I. B. The relation of insulin to liver metabolism. Diabetes 5, 209-222 (1956).
22. Okamoto, H., Obici, S., Accili, D. & Rossetti, L. Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J. Clin. Invest. 115, 1314-1322 (2005).
23. Fisher, S. J. & Kahn, C. R. Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. J. Clin. Invest. 111, 463-468 (2003).
24. LeRoith, D. & Yakar, S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat. Clin. Pract. Endocrinol. Metab. 3, 302-310 (2007).
25. Myers, Jr. M. G. & Olson, D. P. Central nervous system control of metabolism. Nature 491, 357-363 (2012).
26. Gelling, R. W. et al. Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab. 3, 67-73 (2006).
27. Schwartz, M. W. et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503, 59-66 (2013).
28. Inoue, H. et al. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab. 3, 267-275 (2006).
29. Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain-liver circuit regulates glucose homeostasis. Cell Metab. 1, 53-61 (2005).
30. Konner, A. C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438-449 (2007).
31. Ramnanan, C. J. et al. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. J. Clin. Invest. 121, 3713-3723 (2011).
32. Ramnanan, C. J. et al. Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog. Diabetes 62, 74-84 (2013).
33. Lewis, G. F., Vranic, M., Harley, P. & Giacca, A. Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans. Diabetes 46, 1111-1119 (1997).
34. Rebrin, K., Steil, G. M., Mittelman, S. D. & Bergman, R. N. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J. Clin. Invest. 98, 741-749 (1996).
35. Mittelman, S. D. & Bergman, R. N. Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin. Am. J. Physiol. Endocrinol. Metab. 279, E630-E637 (2000).
36. Kawamori, D. et al. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metab. 9, 350-361 (2009).
37. Myers, S. R. et al. Effects of small changes in glucagon on glucose production during a euglycemic, hyperinsulinemic clamp. Metabolism 40, 66-71 (1991).
38. Yecies, J. L. et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 14, 21-32 (2011).
39. Zhou, Y. et al. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat. Med. 17, 356-365 (2011).
40. Bruning, J. C. et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol. Cell 2, 559-569 (1998).
41. Parviz, F. et al. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat. Genet. 34, 292-296 (2003).
42. Miller, R. A. et al. Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. J. Clin. Invest. 121, 2518-2528 (2011).