Physiological concentrations of ketone bodies do not induce browning of white adipocytes/adipose tissue: in vitro and in vivo studies.

Author(s)

Rennan de Oliveira Caminhotto

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2018-10-26

Examining board members

Fabio Bessa Lima; Fabiana de Sant'Anna Evangelista; Jacqueline Luz; Lila Missae Oyama

• Advisor: Fabio Bessa Lima

Abstract

In animals, ketogenic diets induce browning of white adipose tissue, a phenomenon characterized by the increase of adipocytes capable of expressing the uncoupling protein 1 (UCP1) and other markers of brown fat in among white fat. A previous study demonstrated that β-hydroxybutyrate (βHB), the major ketone body, increases markers of the browning process in white adipocytes (in vitro) after 24 hours of incubation. However, the doses tested were supraphysiological (50 mM) or only found during ketoacidosis (25 mM). Ketogenic diets increase ketonemia by about 1-3 mM. Prolonged fasting can increase it to 4-7 mM. Since it could be elicited in vivo through dietary interventions, we studied the impact of physiological concentrations of βHB on metabolism and browning markers on white adipocytes/adipose tissue in different models: adipocytes isolated from Wistar rats, 3T3-L1 cells and in vivo, through the supplementation of βHB salts in Wistar rats. We demonstrate that βHB does not increase any browning markers (such as: oxidative capacity, citrate synthase activity, and browning related genes expression) in isolated adipocytes after 24 or 48 hours of treatment; does not exert a permissive effect on browning induced by β-adrenergic agonism. In addition, 3T3-L1 adipocytes differentiated with βHB (4mM) had a 52% decrease in Ucp1 expression, a result that was reproduced in the subcutaneous inguinal adipose tissue of Wistar rats after ingestion of DL-βHB salts, where Ucp1 expression was undetectable. In conclusion, although the causes of browning of white adipose tissue during ketogenic diets remain inconclusive, our study demonstrates the inability, in physiological concentrations, of ketone bodies themselves to be responsible for this phenomenon. In contrast, in some situations, βHB may impair the expression of Ucp1. (AU)

• FAPESP's process: 14/10705-4 - Effect of beta-hydroxybutyrate in mitochondrial function of isolated white adipocytes
• Grantee: Rennan de Oliveira Caminhotto
• Support Opportunities: Scholarships in Brazil - Doctorate