Protein Kinase G Controls Brown Fat Cell Differentiation and Mitochondrial Biogenesis

Sci. Signal., 1 December 2009
Vol. 2, Issue 99, p. ra78
DOI: 10.1126/scisignal.2000511

Protein Kinase G Controls Brown Fat Cell Differentiation and Mitochondrial Biogenesis

  1. Bodo Haas1,
  2. Peter Mayer2,*,
  3. Katja Jennissen1,*,
  4. Daniela Scholz1,
  5. Mauricio Berriel Diaz3,
  6. Wilhelm Bloch4,
  7. Stephan Herzig3,
  8. Reinhard Fässler5, and
  9. Alexander Pfeifer1,6,
  1. 1Institute for Pharmacology and Toxicology, Biomedical Center, University of Bonn, 53105 Bonn, Germany.
  2. 2Federal Institute for Drugs and Medical Devices, 53175 Bonn, Germany.
  3. 3Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany.
  4. 4Department of Molecular and Cellular Sport Medicine, German Sport University, 50933 Cologne, Germany.
  5. 5Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
  6. 6Pharma-Center, University of Bonn, 53105 Bonn, Germany.
  1. To whom correspondence should be addressed. E-mail: alexander.pfeifer{at}uni-bonn.de
  • * These authors contributed equally to this work.

Abstract

Brown adipose tissue (BAT) is a primary site of energy expenditure through thermogenesis, which is mediated by the uncoupling protein–1 (UCP-1) in mitochondria. Here, we show that protein kinase G (PKG) is essential for brown fat cell differentiation. Induction of adipogenic markers and fat storage was impaired in the absence of PKGI. Furthermore, PKGI mediated the ability of nitric oxide (NO) and guanosine 3′,5′-monophosphate (cGMP) to induce mitochondrial biogenesis and increase the abundance of UCP-1. Mechanistically, we found that PKGI controlled insulin signaling in BAT by inhibiting the activity of RhoA and Rho-associated kinase (ROCK), thereby relieving the inhibitory effects of ROCK on insulin receptor substrate–1 and activating the downstream phosphoinositide 3-kinase–Akt cascade. Thus, PKGI links NO and cGMP signaling with the RhoA-ROCK and the insulin pathways, thereby controlling induction of adipogenic and thermogenic programs during brown fat cell differentiation.

Citation:

B. Haas, P. Mayer, K. Jennissen, D. Scholz, M. B. Diaz, W. Bloch, S. Herzig, R. Fässler, and A. Pfeifer, Protein Kinase G Controls Brown Fat Cell Differentiation and Mitochondrial Biogenesis. Sci. Signal. 2, ra78 (2009).

Inorganic Nitrate Promotes the Browning of White Adipose Tissue Through the Nitrate-Nitrite-Nitric Oxide Pathway
L. D. Roberts, T. Ashmore, A. O. Kotwica, S. A. Murfitt, B. O. Fernandez, M. Feelisch, A. J. Murray, and J. L. Griffin
Diabetes 64, 471-484 (1 February 2015)

ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance
S.-H. Lee, H. Huang, K. Choi, D. H. Lee, J. Shi, T. Liu, K. H. Chun, J. A. Seo, I. S. Lima, J. M. Zabolotny et al.
Am. J. Physiol. Endocrinol. Metab. 306, E332-E343 (1 February 2014)

Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function
H. Maimaitiyiming, Y. Li, W. Cui, X. Tong, H. Norman, X. Qi, and S. Wang
Am. J. Physiol. Renal Physiol. 305, F881-F890 (15 September 2013)

Increased cGMP promotes healthy expansion and browning of white adipose tissue
M. M. Mitschke, L. S. Hoffmann, T. Gnad, D. Scholz, K. Kruithoff, P. Mayer, B. Haas, A. Sassmann, A. Pfeifer, A. Kilic et al.
FASEB J. 27, 1621-1630 (1 April 2013)

A VASP-Rac-Soluble Guanylyl Cyclase Pathway Controls cGMP Production in Adipocytes
K. Jennissen, F. Siegel, M. Liebig-Gonglach, M.-R. Hermann, S. Kipschull, S. van Dooren, W. S. Kunz, R. Fassler, and A. Pfeifer
Sci Signal 5, ra62-ra62 (28 August 2012)

Cyclic GMP Kinase I Modulates Glucagon Release From Pancreatic {alpha}-Cells
V. Leiss, A. Friebe, A. Welling, F. Hofmann, and R. Lukowski
Diabetes 60, 148-156 (1 January 2011)

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action
S. H. Francis, J. L. Busch, and J. D. Corbin
Pharmacol. Rev. 62, 525-563 (1 September 2010)

Cyclic Nucleotides Converge on Brown Adipose Tissue Differentiation
P. S. Amieux, and G. S. McKnight
Sci Signal 3, pe2-pe2 (12 January 2010)

Science Signaling Podcast: 1 December 2009
A. Pfeifer, and A. M. VanHook
Sci Signal 2, pc22-pc22 (1 December 2009)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882