Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome.
Interleukin (IL)-6 is a pleiotropic hormone that has both proinflammatory and anti-inflammatory actions. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that among its other actions responds to decreases in cellular energy state by enhancing processes that generate ATP and inhibiting others that consume ATP but are not acutely necessary for survival. IL-6 is synthesized and released from skeletal muscle in large amounts during exercise, and in rodents, the resultant increase in its concentration correlates temporally with increases in AMPK activity in multiple tissues. That IL-6 may be responsible in great measure for these increases in AMPK is suggested by the fact it increases AMPK activity both in muscle and adipose tissue in vivo and in incubated muscles and cultured adipocytes. In addition, we have found that AMPK activity is diminished in muscle and adipose tissue of 3-month-old IL-6 knockout (KO) mice at rest and that the absolute increases in AMPK activity in these tissues caused by exercise is diminished compared with control mice. Except for an impaired ability to exercise and to oxidize fatty acids, the IL-6 KO mouse appears normal at 3 months of age. On the other hand, by age 9 months, it manifests many of the abnormalities of the metabolic syndrome including obesity, dyslipidemia, and impaired glucose tolerance. This, plus the association of decreased AMPK activity with similar abnormalities in a number of other rodents, suggests that a decrease in AMPK activity may be a causal factor. Whether increases in IL-6, by virtue of their effects on AMPK, contribute to the reported ability of exercise to diminish the prevalence of type 2 diabetes, coronary heart disease, and other disorders associated with the metabolic syndrome remains to be determined.
Ruderman
Neil B
NB
Section of Endocrinology, Diabetes Unit, Boston Medical Center, 650 Albany St., X-820, Boston, MA 02118, USA.
Keller
Charlotte
C
Richard
Ann-Marie
AM
Saha
Asish K
AK
Luo
Zhijun
Z
Xiang
Xiaoqin
X
Giralt
Mercedes
M
Ritov
Vladimir B
VB
Menshikova
Elizabeth V
EV
Kelley
David E
DE
Hidalgo
Juan
J
Pedersen
Bente K
BK
Kelly
Meghan
M
D055372:AMP-Activated Protein Kinases; D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D015444:Exercise / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D024821:Metabolic Syndrome / Q000503:physiopathology; D051379:Mice; D009097:Multienzyme Complexes / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*
D015850:Interleukin-6; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases