The reductions in
body weight peaked at ∼21-28 days post
drug injection and were maintained throughout the study (160 days). The mice ate as much as vehicle-treated control mice. A more potent
SN 28127 analog (
SN 29220) reversed high-fat diet-induced
obesity and
type 2 diabetes in C57BL/6J mice on a high-fat diet.
Insulin induced a sustained reduction in
blood glucose in fasted SN 29220-treated mice compared with the vehicle-treated mice. All
drug-treated mice exhibited a transient increase in water intake from ∼10 days post
drug injection that lasted for ∼70 days. Following a single injection of (3)H-labeled
SN 29220, radioactivity accumulated within 4 h in the liver, bile duct and ileum with little detected in the brain; within 1-2 days, most of the radioactivity was found in the pancreas, spleen, liver, bile duct, stomach, kidneys and white adipose tissue. High levels of
glucose were detected in urine collected from
SN 29220 but not vehicle-treated C57BL/6J mice at ∼60 days post injection, while fecal
triacylglycerols and
cholesterol were not different between
SN 29220 and vehicle-treated mice. These data lead us to hypothesize that the hepatic system is the primary
drug target. Genes involved in
fatty acid synthesis (FASn, SCD1 and PPARĪ³) and appetite stimulation (AGRP) were upregulated at 160 days post
drug treatment, indicative of adaptation to reduced
body weight.
CONCLUSION: We hypothesize that
indoline-derived
drug-induced chronic toxicity to the hepatic system leads to a reduction in white adipose tissue mass. The mice adapt to this
drug-induced toxicity with reduced steady-state
body weight. Understanding molecular mechanisms underlying these responses has potential to identify novel targets for prevention and treatment of
obesity.