EMBO: Obesity represents a global health problem with limited options
available for its prevention or treatment. The finding that a key
regulator of energy expenditure and body weight is controlled by a
drug-targeted inflammatory enzyme opens new possibilities for
pharmacologically modulating body weight. This is the conclusion of a
study led by Toshihiro Nakajima of Tokyo Medical University in Japan,
reported in The EMBO Journal.
Energy spending in human cells is controlled by organelles called
mitochondria, which are the major sites for burning of nutrients such as
fatty acids. Mitochondria therefore play key roles in the fat cells
that form white adipose tissue, an excess of which characterizes
obesity. Earlier research has shown that mitochondrial biogenesis and
fatty acid breakdown is regulated by hormone receptors known as
peroxisome proliferator-activated receptors (PPARs). Pharmacological
activators of PPARs have been tried as promising clinical treatments for
obesity, but such trials have been hindered by undesirable side
effects.
Nakajima’s team had been studying a gene called Synoviolin, which is
causally linked to the inflammatory condition of rheumatoid arthritis.
In previous work, they developed a chemical compound, LS-102, that
inhibits the enzyme encoded by the Synoviolin gene and suppresses
rheumatoid arthritis in mouse disease models. Given the close
associations of inflammation and metabolic diseases, including obesity
and diabetes, the authors now tested the role of the Synoviolin gene in
mouse models for such disorders. Loss of Synoviolin led to decreased
white fat tissue and reduced body weight, which was traced to
mitochondrial up-regulation. Importantly, the authors could show that
loss or inhibition of SYVN1, the enzyme encoded by the Synoviolin gene,
led to stabilization of an endogenous cellular PPAR activator, thus
turning on PPAR-dependent energy control pathways. Therefore, treatment
with the LS-102 inhibitor may provide an alternative to the side
effect-troubled chemical PPAR activators for treating obese patients.
“Obesity is a known risk factor for other chronic disorders,” says
Nakajima. “Our findings indicate that Synoviolin may be a key for
understanding the common features of obesity and chronic inflammatory
disease such as rheumatoid arthritis.”
The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1β
Fujita H, Yagishita N, Aratani S, Saito-Fujita T, Morota S, Yamano Y,
Hansson MJ, Inazu M, Kokuba H, Sudo K, Sato E, Kawahara K, Nakajima F,
Hasegawa D, Higuchi I, Sato T, Araya N, Usui C, Nishioka K, Nakatani Y,
Maruyama I, Usui M, Hara N, Uchino H, Elmer E, Nishioka K, Nakajima T
Read the article: http://emboj.embopress.org/content/early/2015/02/17/embj.201489897
Further information on The EMBO Journal is available at emboj.embopress.org