Title:
Importance of Metabolic Interaction between Adipose Tissue and Liver in the Maintenance of Glucose Homeostasis.

Takashi Miki
Department of Medical Physiology, Medicine Chiba University Graduate School of Medicine

Abstract:
Rapid increase in the prevalence of type 2 diabetes mellitus (T2DM) worldwide is considered to be attributable to the changes in environmental factors, including less physical activity and overnutrition along with a shift in nutrient composition.  Especially, excessive fat intake is known to promote the onset of T2DM in humans and rodents.  Nevertheless, the pathophysiology of high fat diet (HFD)-induced diabetes mellitus has not been fully clarified, due to the lack of ideal animal models that develop overt hyperglycemia in response to HFD.
  Heterozygous mutant (Insr^P1195L/+) mice exhibit insulin resistance but escape from any glucose intolerance even by glucose loading test.  Interestingly, we found that Insr^P1195L/+ mice developed overt hyperglycemia and the mechanism for HFD-induced hyperglycemia was elucidated inInsr^P1195L/+ mice.  By analyzing the metabolic changes in various tissues, we found that the lipolysis in white adipose tissues (WAT) was markedly increased Insr^P1195L/+ mice under HFD (Insr^P1195L/+/HFD), leading to the increased glycerol release from WAT.  In addition, gluconeogenesis from glycerol was shown to be increased in Insr^P1195L/+ mice only under HFD conditions.  Therefore, combination of increased lipolysis in WAT and increased gluconeogensis from glycerol in liver triggers the HFD-induced hyperglycemia in Insr^P1195L/+ mice.  Considering that lipolysis in WAT is increased in type 2 diabetes patients, the suppression of lipolysis could be a novel molecular target for its treatment.