A novel, centrally acting mammalian aminosterol, ENT-03, induces weight loss in obese and lean rodents.
Denise BarbutWilliam A KinneyHsiao-Huei ChenAlexandre F R StewartJacob Hecksher-SørensenChen ZhangAlexander FlemingMichael ZemelMichael ZasloffPublished in: Diabetes, obesity & metabolism (2024)
ENT-03, a spermine bile acid we recently discovered in the brain of newborn mice acts centrally to regulate energy and metabolism. Obese, diabetic (ob/ob) mice treated with five doses of ENT-03 over 2 weeks, demonstrated a rapid decrease in blood glucose levels into the range seen in non-obese animals, prior to any significant weight loss. Weight fell substantially thereafter as food intake decreased, and serum biochemical parameters normalized compared with both vehicle and pair-fed controls. To determine whether ENT-03 could be acting centrally, we injected a single dose of ENT-03 intracerebroventricularly to Sprague-Dawley rats. Weight fell significantly and remained below vehicle injected controls for an extended period. By autoradiography, ENT-03 localized to the arcuate nucleus of the hypothalamus, the choroid plexus and cerebrospinal fluid. Significant cFos activation occurred in multiple anatomical regions within the hypothalamus and brainstem involved in appetite suppression, food-entrained circadian rhythmicity, autonomic function, and growth. These data support a role for ENT-03 in the treatment of type 2 diabetes and obesity. Phase 1 studies in subjects with obesity and diabetes are currently in progress.
Keyphrases
- weight loss
- bariatric surgery
- glycemic control
- roux en y gastric bypass
- blood glucose
- gastric bypass
- type diabetes
- high fat diet induced
- weight gain
- cerebrospinal fluid
- obese patients
- cardiovascular disease
- adipose tissue
- insulin resistance
- body mass index
- brain injury
- heart rate variability
- blood pressure
- multiple sclerosis
- big data
- ultrasound guided
- electronic health record
- bone mineral density
- climate change
- skeletal muscle
- heart rate
- quantum dots
- loop mediated isothermal amplification