The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 8 • September 2013


Increasing cGMP Promotes the Expansion and
Browning of White Adipose Tissue

A Brite Future for the Treatment of Obesity

A remarkable new discovery1 published this year reports that increasing cyclic GMP (cGMP) signaling can cause white adipose tissue to develop the properties of “brown-like” or “brite” (also sometimes called beige) fat tissue that, like brown adipose tissue (BAT), uncouple mitochondrial metabolism from ATP synthesis to the generation of heat (thermogenesis) via UCP-1 (uncoupling protein 1). Also, like brown adipose tissue, the browned white adipose tissue have larger numbers of mitochondria than white adipose tissue and also increased insulin sensitivity. The authors1 suggest (and we agree) that browning white adipose tissue is a potential treatment for obesity.

One way to increase cGMP is with phosphodiesterase 5 inhibitors (which inhibit the degradation of cGMP) such as those used in the treatment of erectile dysfunction. Some of the experiments in this paper1 tested the effects of sildenafil (Viagra®) as a browning agent. (Note: Cialis® is another phosphodiesterase 5 inhibitor, which however has a far longer half-life than sildenafil; we expect that it would have similar effects on browning white adipose tissue though the effect of the longer half-life is unclear but might be expected to be advantageous. Further testing will provide answers.)

The researchers studied the effect of cGMP signaling, focusing on cGMP-dependent protein kinase I (PKGI), which is expressed in white adipose tissue. By inducing overexpression of PKGI, there was a 4.3 fold increase in the abundance of UCP-1, uncoupling protein 1, the uncoupling protein found in brown adipose tissue (BAT) that is part of BAT’s thermogenic program. Importantly, “treatment of DC57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 days caused 4.6 fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype (“browning”) of WAT in vivo.”1 The basal expression of PKGI in white adipose tissue is negligible.1 “Our study clearly shows that activation of PKGI in adipocytes increases adiponectin expression and, in parallel, decreases gene expression of proinflammatory cytokines (MCP1, CCL3, CCL7, IL6, and TNFA).”1

The researchers also investigated the effects of a demethylating agent, 5-aza-deoxycytidine, on the UCP-1 gene promoter. They found that the treatment of 3T3-LI adipocytes with this drug increased basal levels of UCP-1 mRNA levels, which (they also report) were even further increased in cells expressing high levels of PKGI treated with cGMP. Moreover, the expression of adiponectin by the 3T3-LI adipocytes treated with cGMP was increased and this effect was also further increased in cells overexpressing PKGI. The expression of PGC-1alpha, a “master” regulator of mitochondrial biosynthesis, was also increased in the white adipose tissue of mice treated with sildenafil.

Possible Enhanced Expression of UCP1 With Curcumin or EGCG

In a separate paper,3 the UCP1 gene was demethylated by 5-aza-deoxycytidine that increased the expression of the gene. The natural substances curcumin4 and EGCG5 have been found to be demethylating agents and might, therefore, have similar effects to that of 5-Aza-deoxycytidine by increasing basal levels of UCP-1 mRNA. If so, these substances may also act as “browning” agents. We expect to see papers published on these effects, should they be revealed in new experiments, following hot on the heels of these new findings on UCP1 demethylation.

The bottom line is that both cGMP and sildenafil promote browning of white adipose tissue. The effect, the authors say, can be induced by phosphodiesterase 5 or phosphodiesterase 3B inhibitors, via increase in cGMP or cAMP (cyclic AMP). The researchers cite a study in which 12 weeks of sildenafil (Viagra) treatment of normal mice fed a high fat diet reduced body weight and improved energy balance.2

In their “Discussion” section in the paper,1 the authors note that cGMP has been shown to regulate glucagon secretion (and, thus, gluconeogenesis by the liver), mitochondrial biogenesis, and the development of “classical” BAT (brown adipose tissue). Out-of-control gluconeogenesis, that is, excessive release of glucose by the liver (which is supposed to be suppressed by insulin following a meal), is a major cause of the hyperglycemia of diabetes.

We look forward to a “brite” future that may result from the treatment of obesity with compounds that increase cGMP.

References

  1. Mitschke et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27:1621-30 (2013).
  2. Ayala et al. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes. 56:1025-33 (2007).
  3. Shore et al. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia. 53:1164-73 (2010).
  4. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
  5. Fang et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563-7570 (2003).

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