Characterization of endogenous bile acid composition in individuals with cold-activated brown adipose tissue

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Abstract

Introduction

Bile acid signaling has been suggested to promote BAT activity in various experimental models. However, little is known if and how physiologic bile acid metabolism is linked to BAT function in humans. Here we investigated the association between BAT activity and circulating bile acid concentrations in lean and obese individuals.

Methods

BAT 18F-fluorodeoxyglucose uptake was measured after a standardized cooling protocol by positron emission tomography/computed tomography. Cold-induced thermogenesis was assessed by indirect calorimetry. Fasting bile acid concentrations were determined by high performance liquid chromatography–high-resolution mass spectrometry.

Results

In a cohort of 24 BAT-negative and 20 BAT-positive individuals matched by age, sex, and body mass index, circulating bile acid levels were similar between groups except for higher ursodeoxycholic acid and a trend towards a lower 12α-OH/non-12α-OH bile acid ratio in lean participants with active BAT compared to those without. Moreover, the 12α-OH/non-12α-OH ratio, a marker of CYP8B1 activity, correlated negatively with BAT volume and activity.

Conclusion

Fasting concentrations of major bile acids are not associated with cold-induced BAT activity in humans. However, the inverse association between BAT activity and 12α-OH/non-12α-OH ratio may suggest CYP8B1 as a potential new target in BAT function and warrants additional investigation.

Introduction

Due to its energy dissipating qualities, brown adipose tissue (BAT) has emerged as a promising therapeutic target for the treatment of obesity and related sequelae. Activation of BAT in humans results in increased energy expenditure, improves insulin sensitivity and lipid metabolism (Chondronikola et al., 2016; Iwen et al., 2017; van Marken Lichtenbelt et al., 2009). BAT recruitment by means of chronic cold exposure also reduced body fat mass (Yoneshiro et al., 2013). However, little is known about the endogenous regulation of BAT activity. Recently, bile acid metabolism has been linked to BAT function. It has been suggested that bile acids could exert beneficial metabolic effects through the G protein-coupled bile acid receptor TGR5 or the nuclear farnesoid x receptor (FXR) with variable affinities of different bile acid species for these receptors (Chen et al., 2011; de Aguiar Vallim et al., 2013; Shapiro et al., 2018). TGR5 is expressed on adipocytes and increases thermogenesis by interacting with the thyroid hormone-converting enzyme type II iodothyronine deiodinase (Watanabe et al., 2006). Intestinal FXR agonism promoted adipose tissue browning in mice and reduced insulin resistance and obesity (Fang et al., 2015). Cholic acid administration in mice induced expression of uncoupling protein-1 in BAT, increased energy turnover and reduced adiposity (Zietak and Kozak, 2016). In humans, short-term treatment with the primary bile acid chenodeoxycholic acid resulted in enhanced BAT activity and energy expenditure (Broeders et al., 2015). A study in mice reported that cold exposure leads to increased bile acid concentrations which mediate an expansion of BAT activity (Worthmann et al., 2017).

Previous studies reported that obesity is itself associated with an increased bile acid synthesis, especially increased 12α-OH bile acids (cholic acid and deoxycholic acid) through CYP8B1, as well as an impaired hepatic sinusoidal transport (Haeusler et al, 2013, 2016). Thus obesity-induced alterations in bile acid concentrations could serve as a negative feedback mechanism by increasing BAT activity.

Given these observations, we aimed to establish the association between endogenous circulating bile acids and cold-induced BAT activity in a population of both lean and obese but otherwise healthy adults.

Section snippets

Population

We included participants of two prospective studies investigating BAT activity in healthy subjects who are lean or obese (cohort 1, NCT02381483) as well as subjects with morbid obesity (cohort 2, NCT03168009). Inclusion criteria included age between 18 and 50 years and a body mass index either between 18.5 and 25 kg/m2 (lean) or 30 and 55 kg/m2 (obese). The exclusion criteria included endocrinological disease except substituted hypothyroidism, chronic kidney disease, chronic liver disease,

Metabolic parameters did not differ between age-, sex- and BMI-matched individuals with and without active BAT

Of the 45 participants included in this study, one was excluded because of fasting bile acid levels above the commonly accepted upper normal limit for healthy adults of 10 μmol/L. This resulted in a total cohort of 20 subjects with (BATpos) and 24 without (BATneg) active BAT. By design of the study, the BATneg and BATpos participants did not differ by age, sex, or body composition (Table 1). Important metabolic parameters such as blood glucose, cholesterol and triglycerides were similar in both

Discussion

An increasing body of evidence suggests that bile acids are critical regulators of energy metabolism pathways including thermogenic processes in adipocytes (Broeders et al., 2015; Fang et al., 2015; Velazquez-Villegas et al., 2018; Watanabe et al., 2006; Zietak and Kozak, 2016). The emerging importance of BAT as an energy dissipating metabolic organ has spurred efforts to elucidate if BAT activation confers health benefits in humans and how energy metabolism may differ between individuals with

Funding

This work was supported by the Austrian Science Fund (FWF) P 27391-B26 and the Medical-Scientific Fund of the Mayor of the City of Vienna 17094, and the Austrian Diabetes Association Research Fund all to FWK.

Declaration of competing interest

The authors declare no conflict of interest.

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