- The study of adipocytes from obese specimens
- The physiological and pathological roles of adipocytokines
The mechanism of adipocyte homeostasis and its dysfunction in metabolic diseases
Adipose cells accumulate in conditions of excess energy and release energy when there is a deficit. Thus, they maintain homeostasis when the body is feeding, fasting or even starving. Like many rich countries, the Japanese population is eating and exercising at levels that is causing a rise in overall daily caloric intake. The result is an increase in diabetes, dyslipidemia, and metabolic syndrome. To understand how these lifestyle diseases develop, it is important to understand the physiological function and pathogenesis of adipocytes. Accordingly, we are investigating adipose tissue and the function of adipocytokines.
1) Pathology of adipose tissue in obesity
Adipose tissue in obesity show a high level of reactive oxygen species (ROS) and low levels of antioxidant species, indicating a state of oxidative stress1. In general, obese patients and mice show more fat tissue ROS (FatROS). Phenotypes of this condition include adipocytokine dysregulation and insulin resistance. Additionally, there is an increase in visceral fat levels, a loss of neutral fats in subcutaneous fat tissue, and suppression of fatty acid synthase2.
Furthermore, the body cannot provide enough blood to sustain the increased adipocyte size seen in obese tissue, resulting in a hypoxic state3. Consistent with obesity, hypoxic adipocytes show adipocytokine dysregulation and insulin resistance.
Finally, Treg are T cells that regulate the immune response by suppressing the activity of effector T cells. These cells are normally abundant in normal adipose tissue, but are at much lower levels in obese tissue. It is believed that macrophages in the tissues regulate the differentiation and proliferation of Treg4. So too do eicosaentaenoic acid metabolites5.
2) Functional analysis of adipocytokines
Adipocytes produce the chemokine SDF-1, which reduces insulin sensitivity of the adipocytes6. Indeed, in obese tissue, the production of SDF-1 is abnormally high.
Favine is a secretory factor produced by adipocytes and blood vessels7. It functions to differentiate adipocytes and accumulate neutral fat8. Unlike normal mice, aged mice deficient of Favine are remarkably thin and do not develop fatty livers.
Finally, adiponectin is an adipocytokine that binds to T-cadherin expressed on blood vessels9. This binding causes the endothelial cells to produce exosomes10. These exosomes contain several factors responsible for vascular homeostasis.
1. Furukawa S, et al. J. Clin. Invest. 114 (12): 1752-1761, 2004.
2. Okuno Y, et al. Diabetes 67 (6): 1113-1127, 2018.
3. Hosogai N, et al. Diabetes 56 (4): 901-911, 2007.
4. Onodera T, et al. Sci. Rep. 5 16801, 2015.
5. Onodera T, et al. Sci. Rep. 7 (1): 4560, 2017.
6. Shin J, et al. Diabetes 67 (6): 1068-1078, 2018.
7. Kobayashi S, et al. Biochem. Biophys. Res. Commun. 392 (1): 29-35, 2010.
8. Kobayashi S, et al. J. Biol. Chem. 290 (12): 7443-7451, 2015.
9. Fukuda S, et al. J. Biol. Chem. 292 (19): 7840-7849, 2017.
10. Obata Y, et al. JCI Insight 3 (8): e99680, 2018.