TY - JOUR
T1 - Lipolytic effects of 3-iodothyronamine (T1AM) and a novel thyronamine-like analog SG-2 through the AMPK pathway
AU - Rogowski, Michael
AU - Bellusci, Lorenza
AU - Sabatini, Martina
AU - Rapposelli, Simona
AU - Rahman, Shaikh M.
AU - Chiellini, Grazia
AU - Assadi-Porter, Fariba M.
N1 - Funding Information:
Funding: This research was funded by NIH grants R01 DC009018 to FAP, and in part by Achievement Awards for College Scientists Scholarship Organization, Lubbock, TX 2015, and by University of Pisa Research Grant 2017-18 (PRA_2017_55) to GC, and in Part by CERES Foundation to FAP.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/8/2
Y1 - 2019/8/2
N2 - 3-Iodothyronamine (T1AM) and its synthetic analog SG-2 are rapidly emerging as promising drivers of cellular metabolic reprogramming. Our recent research indicates that in obese mice a sub-chronic low dose T1AM treatment increased lipolysis, associated with significant weight loss independent of food consumption. The specific cellular mechanism of T1AM’s lipolytic effect and its site of action remains unknown. First, to study the mechanism used by T1AM to gain entry into cells, we synthesized a fluoro-labeled version of T1AM (FL-T1AM) by conjugating it to rhodamine (TRITC) and analyzed its cellular uptake and localization in 3T3-L1 mouse adipocytes. Cell imaging using confocal microscopy revealed a rapid intercellular uptake of FL-T1AM into mitochondria without localization to the lipid droplet or nucleus of mature adipocytes. Treatment of 3T3-L1 adipocytes with T1AM and SG-2 resulted in decreased lipid accumulation, the latter showing a significantly higher potency than T1AM (10 µM vs. 20 µM, respectively). We further examined the effects of T1AM and SG-2 on liver HepG2 cells. A significant decrease in lipid accumulation was observed in HepG2 cells treated with T1AM or SG-2, due to increased lipolytic activity. This was confirmed by accumulation of glycerol in the culture media and through activation of the AMPK/ACC signaling pathways.
AB - 3-Iodothyronamine (T1AM) and its synthetic analog SG-2 are rapidly emerging as promising drivers of cellular metabolic reprogramming. Our recent research indicates that in obese mice a sub-chronic low dose T1AM treatment increased lipolysis, associated with significant weight loss independent of food consumption. The specific cellular mechanism of T1AM’s lipolytic effect and its site of action remains unknown. First, to study the mechanism used by T1AM to gain entry into cells, we synthesized a fluoro-labeled version of T1AM (FL-T1AM) by conjugating it to rhodamine (TRITC) and analyzed its cellular uptake and localization in 3T3-L1 mouse adipocytes. Cell imaging using confocal microscopy revealed a rapid intercellular uptake of FL-T1AM into mitochondria without localization to the lipid droplet or nucleus of mature adipocytes. Treatment of 3T3-L1 adipocytes with T1AM and SG-2 resulted in decreased lipid accumulation, the latter showing a significantly higher potency than T1AM (10 µM vs. 20 µM, respectively). We further examined the effects of T1AM and SG-2 on liver HepG2 cells. A significant decrease in lipid accumulation was observed in HepG2 cells treated with T1AM or SG-2, due to increased lipolytic activity. This was confirmed by accumulation of glycerol in the culture media and through activation of the AMPK/ACC signaling pathways.
KW - 3-iodothyronamine (T1AM)
KW - AMPK pathway
KW - Cell imaging
KW - Lipid metabolism
KW - Metabolic reprogramming
KW - Mitochondria
KW - Rhodamine (TRITC)
KW - Thyroid hormone analogs
UR - http://www.scopus.com/inward/record.url?scp=85071247925&partnerID=8YFLogxK
U2 - 10.3390/ijms20164054
DO - 10.3390/ijms20164054
M3 - Article
C2 - 31434215
AN - SCOPUS:85071247925
SN - 1661-6596
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 16
M1 - 4054
ER -