title: Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models.
abstract: OBJECTIVE
  Tofogliflozin, a highly selective inhibitor of sodium/glucose cotransporter 2 (SGLT2), induces urinary glucose excretion (UGE), improves hyperglycemia and reduces body weight in patients with Type 2 diabetes (T2D). The mechanisms of tofogliflozin on body weight reduction were investigated in detail with obese and diabetic animal models.
  
  
  METHODS
  Diet-induced obese (DIO) rats and KKAy mice (a mouse model of diabetes with obesity) were fed diets containing tofogliflozin. Body weight, body composition, biochemical parameters and metabolic parameters were evaluated.
  
  
  RESULTS
  In DIO rats tofogliflozin was administered for 9 weeks, UGE was induced and body weight gain was attenuated. Body fat mass decreased without significant change in bone mass or lean body mass. Food consumption (FC) increased without change in energy expenditure, and deduced total calorie balance (deduced total calorie balance=FC-UGE-energy expenditure) decreased. Respiratory quotient (RQ) and plasma triglyceride (TG) level decreased, and plasma total ketone body (TKB) level increased. Moreover, plasma leptin level, adipocyte cell size and proportion of CD68-positive cells in mesenteric adipose tissue decreased. In KKAy mice, tofogliflozin was administered for 3 or 5 weeks, plasma glucose level and body weight gain decreased together with a reduction in liver weight and TG content without a reduction in body water content. Combination therapy with tofogliflozin and pioglitazone suppressed pioglitazone-induced body weight gain and reduced glycated hemoglobin level more effectively than monotherapy with either pioglitazone or tofogliflozin alone.
  
  
  CONCLUSIONS
  Body weight reduction with tofogliflozin is mainly due to calorie loss with increased UGE. In addition, tofogliflozin also induces a metabolic shift from carbohydrate oxidation to fatty acid oxidation, which may lead to prevention of fat accumulation and inflammation in adipose tissue and liver. Tofogliflozin may have the potential to prevent obesity, hepatic steatosis and improve insulin resistance as well as hyperglycemia.
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kito
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fukazawa
authors.affiliation: Chugai Research Institute for Medical Science Inc. Gotemba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yata
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nagata
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fukuzawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamane
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawabe