<総説>日本にヒューマン・カロリメーターができて20 年

The first metabolic chamber for human subjects in Japan was built in 2000 in National Institute of Health and Nutrition.In 2019, 19 metabolic chambers, including 4 chambers in the University of Tsukuba, have been built in Japan. Now, China is catching up with us importing metabolic chambers from Japan, which seems to approve our decision back in 2003 to improve time resolution of the system. This is a personal account on the history of metabolic chamber, which is also known as a whole room indirect calorimeter or human calorimeter, during the recent 20 years. Funded by COE program, the second metabolic chamber in Japan was built in University of Tsukuba in 2003. In our system, an online mass spectrometer was installed and a new algorithm was developed to improve transient response of metabolic chamber. Currently, time resolution of our system is the best in the world. Using our system, it was shown that 1) effect of exercise to increase accumulated fat oxidation during 24 h depends on when the exercise is performed, 2) energy metabolism during sleep differs among sleep stages, 3) energy expenditure and RQ decrease during the first half of sleep followed by a gradual increase prior to awakeni

Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity

M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity

LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance

Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance. © 2014 by the American Diabetes Association