title: Chronic hyperinsulinemia reduces insulin sensitivity and metabolic functions of brown adipocyte.
abstract: The growing pandemics of diabetes have become a real threat to world economy. Hyperinsulinemia and insulin resistance are closely associated with the pathophysiology of type 2 diabetes. In pretext of brown adipocytes being considered as the therapeutic strategy for the treatment of obesity and insulin resistance, we have tried to understand the effect of hyperinsulinemia on brown adipocyte function. We here with for the first time report that hyperinsulinemia-induced insulin resistance in brown adipocyte is also accompanied with reduced insulin sensitivity and brown adipocyte characteristics. CI treatment decreased expression of brown adipocyte-specific markers (such as PRDM16, PGC1α, and UCP1) and mitochondrial content as well as activity. CI-treated brown adipocytes showed drastic decrease in oxygen consumption rate (OCR) and spare respiratory capacity. Morphological study indicates increased accumulation of lipid droplets in CI-treated brown adipocytes. We have further validated these findings in vivo in C57BL/6 mice implanted with mini-osmotic insulin pump for 8weeks. CI treatment in mice leads to increased body weight gain, fat mass and impaired glucose intolerance with reduced energy expenditure and insulin sensitivity. CI-treated mice showed decreased BAT characteristics and function. We also observed increased inflammation and ER stress markers in BAT of CI-treated animals. The above results conclude that hyperinsulinemia has deleterious effect on brown adipocyte function, making it susceptible to insulin resistance. Thus, the above findings have greater implication in designing approaches for the treatment of insulin resistance and diabetes via recruitment of brown adipocytes.
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India Academy of Scientific and Innovative ResearchCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Sujith
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Kripa
authors.initials: K
authors.lastname: Shankar
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Muheeb
authors.initials: M
authors.lastname: Beg
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Salil
authors.initials: S
authors.lastname: Varshney
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India Academy of Scientific and Innovative ResearchCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India Academy of Scientific and Innovative ResearchCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Durgesh
authors.initials: D
authors.lastname: Kumar
authors.affiliation: SIPS Superspeciality HospitalLucknow, Uttar Pradesh, India.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Division of PharmacokineticsCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Zakir
authors.initials: Z
authors.lastname: Hussain
authors.affiliation: Division of PharmacokineticsCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.affiliation: Division of PharmacologyCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India Academy of Scientific and Innovative ResearchCSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India anil_gaikwad@cdri.res.in.
authors.forename: Anil N
authors.initials: AN
authors.lastname: Gaikwad
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002454:Cell Differentiation; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D014157:Transcription Factors / Q000378:metabolism; D015430:Weight Gain / Q000502:physiology
chemical_list: D014157:Transcription Factors
keywords: brown adipocytes; differentiation; human mesenchymal stem cells; insulin; insulin resistance