The administration of an extract from Berberis microphylla stimulates energy expenditure, thermogenesis and mitochondrial dynamics in mice brown adipose tissue

Highlights

• A polyphenol-rich Calafate extract prevented diet-induced obesity in mice.

• This prevention is associated with high energy expenditure.

• Also recovers blunted brown adipose tissue mitochondrial function and dynamics.

Abstract

Obesity is defined as excess fat accumulation in white adipose tissue. In opposition to this storage function, brown adipose tissue (BAT) counters obesity, by consuming fat through thermogenesis. Obese individuals display lower BAT mitochondrial oxidative capacity and altered mitochondrial morphology. A promising strategy to fight obesity is dietary polyphenols, which increase BAT mass and function, stimulating energy expenditure (EE). Calafate, a polyphenol-rich Chilean native fruit, has anti-inflammatory and antioxidant characteristics. The effect of a Calafate extract (50 mg [total polyphenols]/kg body weight/day) on EE and mitochondrial function and morphology in BAT from obese mice was assessed. Adult male C57BL/6J mice were subdivided into four treatments for 18 weeks: control diet (C), control diet + Calafate (CC), high-fat diet (HF), high-fat diet + Calafate (HFC). Calafate extract decreased high-fat diet-induced body weight gain from week 6 of treatment (p<0,05) and increased EE at rest (p = 0.03). In BAT, Calafate extract reversed the decrease in UCP-1 protein levels generated by the high-fat diet (p = 0.004). Also, Calafate extract improved mitochondrial transmembrane potential (p = 0.04). The extract did not substantially modify mitochondrial morphology, although it increased the expression of optic atrophy protein 1 (p = 0.01), a mitochondrial fusion-related protein. In sum, consumption of a polyphenol-rich Calafate extract prevents high-fat diet-induced obesity, concomitant with higher energy expenditure, and improved BAT mitochondrial function in obese mice.

Introduction

The quick epidemiologic transition to obesity is a critical public health problem nowadays. Obesity is defined as abnormal or excessive adipose tissue accumulation that could be harmful to health (WHO, 2020). The white adipose tissue (WAT) is the main energetic reservoir of the organism. Human adults present another adipose tissue, the brown adipose tissue (BAT). BAT occurs on less quantity than WAT, and in restricted to discrete anatomical sites (Ravussin et al., 2011). Brown adipocytes have multilocular lipid droplets, a central oval nucleus, and a large number of mitochondria, characterized by expressing uncoupling protein 1 (UCP1) (Cannon et al., 2004). UCP1 is a proton transporter located in the inner mitochondrial membrane, which allows translocation of protons from the intermembrane space to the mitochondrial matrix to dissipate energy as heat, at the expense of ATP production (Bertholet et al., 2017). UCP1 is the main effector of thermogenesis in BAT, allowing brown adipocytes to rapidly oxidize fat reserves and circulating substrates, increasing the basal metabolic rate (Heaton et al., 1978). Obesity have been reported to be associated with a decreased BAT mass and activity in humans (Leitner et al., 2017). Mitochondria of obese individuals (compared to lean) have less defined internal membranes, reduced fatty acid oxidation, and less heat generation capacity (Hernandez-Aguilera et al., 2013).

Mitochondrial morphology is also a key element of their function. Alterations in dynamics of mitochondrial morphology may involve oxidative stress, mitochondrial dysfunction, and metabolic disturbances (Rovira-Llopis et al., 2017). In this regard, optic atrophy protein 1 (OPA1) located in the intermembrane space, participates in maintaining the structure of mitochondrial cristae, as well as the merging of the internal membranes during mitochondrial fusion (Olichon et al., 2002). On the other hand, mitochondrial fission is mediated by fission protein 1 and the mitochondrial fission factor at the outer membrane level, which recruit the dynamin-related protein 1 (DRP1) as the molecular motor for fission (Wikstrom et al., 2014).

Different bioactive components of foods with cardioprotective, antioxidant, and/or anti-inflammatory properties have been studied. One potential target of these compounds is BAT, through the induction of thermogenesis and the improvement of mitochondrial function. One of the most studied group of bioactive compounds regarding obesity are polyphenols. The activity of polyphenols on cellular energy metabolism is widely known, gathering anti-obesogenic and pro-thermogenic characteristics (Mele et al., 2017). It is widely established berries as a major source of these compounds (Mazzoni et al., 2016), and among them Berberis microphylla (commonly named as Calafate), an endemic fruit of Patagonia, is characterized by its high content of polyphenols, particularly anthocyanins (Fredes et al., 2020). Its effects have been reported in vitro, in mice and human cells, where an extract of Calafate modulated the pro-inflammatory crosstalk adipocyte-macrophage (Ovalle-Marin et al., 2020; Reyes-Farias et al., 2015, 2016). Besides, it has been shown to restore glucose tolerance in obese animals (Soto-Covasich et al., 2020). Our objective was to test a purified and characterized Calafate extract as treatment for high fat diet induced obesity in mice, by exploring mitochondrial respiration, energy expenditure, and mitochondrial dynamics modulation in BAT.