Cell Metabolism

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Come on BAIBA Light My Fire

Helene L. Kammoun1 and Mark A. Febbraio1,*1Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Victoria, Australia*Correspondence: mark.febbraio@bakeridi.edu.auhttp://dx.doi.org/10.1016/j.cmet.2013.12.007

The contracting muscle has been shown to act as an endocrine organ, secreting ‘‘myokines’’ that participatein tissue crosstalk. In this issue of Cell Metabolism, Roberts et al. (2014) identify BAIBA as a contraction-induced myokine that results in browning of white adipose tissue and increases fat oxidation in the liver.

Over the last decade, it has become clear

that skeletal muscle can act as an endo-

crine organ that secretes several cyto-

kines and peptides termed ‘‘myokines’’

(Pedersen and Febbraio, 2012). Physical

activity protects against all causes of

mortality (Blair et al., 1995), and the iden-

tification of skeletal muscle as an endo-

crine organ (Febbraio et al., 2004)

provided mechanistic insight into the

disease-preventative effects of regular

physical activity, which include weight

loss in obese or overweight people. In

this issue of Cell Metabolism, Roberts

et al. (2014) demonstrate that the con-

tracting muscle cells secrete the metabo-

lite b-aminoisobutyric acid (BAIBA), which

mediates signaling processes in white

adipose tissue (WAT) and liver, leading

to weight loss and enhanced glucose

tolerance in mice (Roberts et al., 2014).

Peroxisome proliferator-activated re-

ceptor g coactivator-1a (PGC1a) is a

master transcriptional coactivator that

appears to be obligatory in the control of

energy metabolism (Handschin and Spie-

gelman, 2008). Initially discovered for its

role in promoting the thermogenic pro-

graming of brown adipose tissue (BAT),

PGC1a was subsequently identified as a

major regulator of skeletal muscle fiber

type, crucial in the adaptation of this

organ to exercise (Handschin and Spie-

gelman, 2008). However, the observation

that muscle-specific PGC1a-deficient

mice displayed a b cell phenotype (Hand-

schin et al., 2007) prompted the Spiegel-

man laboratory to investigate whether

this effect was due to the secretion of

one or more myokines. Indeed, Bostrom

et al. (2012) demonstrated that the con-

tracting skeletal muscle secreted Irisin,

a cleaved product of the protein fibro-

nectin type 3 domain-containing protein

5 (FNDC5), into the blood in a PGC1a-

dependent manner (Bostrom et al.,

2012). This work from the Spiegelman

group demonstrated that Irisin could act

as a fat ‘‘browning’’ agent by promoting

the development of brown-like adipo-

cytes within subcutaneousWAT (Bostrom

et al., 2012). Given that BAT can oxidize

high levels of glucose and lipids to

generate heat, the activation or the devel-

opment of BAT in humans holds high

potential as a therapy for metabolic dis-

eases (Cannon and Nedergaard, 2004).

In light of these previous observations,

Roberts et al. (2014) sought to determine

if any additional mechanisms were in-

volved in mediating tissue crosstalk from

skeletal muscle to other organs during

muscle contraction. Using the same initial

model of exercise-mimicking myocytes

overexpressing PGC1a, the authors an-

alyzed the myocyte secretome through a

liquid chromatography-mass spectrom-

etry metabolic profiling technique. This

approach identified four metabolites that

were significantly increased in the high-

PGC1a conditions (Roberts et al., 2014).

These metabolites were then added to

primary adipocytes derived from subcu-

taneous inguinal fat pads to test their

ability to act on fat tissue. One such

secretory factor, a metabolite derived

from valine and thymine catabolism,

BAIBA, potentiated the expression of

brown adipocyte-specific genes such as

Uncoupled Protein-1 (UCP1) and Cell

Death-Inducing DFFA-like effector a

(CIDEA).

The authors then confirmed that the

addition of BAIBA to human induced

pluripotent stem cells, under conditions

that would normally result in white adipo-

cyte differentiation, instead led to a brown

adipocyte-like gene expression signature.

Moreover, functional in vitro measures,

such as cellular glucose uptake and

respiratory capacity, were also affected.

Importantly, the authors recapitulated

Cell Metabolism

these findings in vivo by demonstrating

that muscle-specific PGC1a overexpres-

sion or, indeed, exercise increases the

circulating BAIBA concentration in mice.

In addition, BAIBA treatment in vivo led

to increased BAT-specific gene expres-

sion in the inguinal WAT, and this was

associated with decreased weight gain

and improved glucose tolerance in diet-

induced obese mice. The authors also

described enhanced b-oxidation in the

liver of BAIBA-treated animals but did

not report whether there was a subse-

quent improvement in hepatic steatosis

in the long-term-treated animals on a

high-fat diet, something that would be

of great interest. Interestingly, Roberts

et al. (2014) demonstrated that the effects

of BAIBA in both liver and adipose tissue

were dependent upon peroxisome pro-

liferator-activated receptor a (PPARa)

expression, a transcription factor not

only known as a master regulator of

b-oxidation but also reported to stimulate

the expression of UCP1 (Lee et al., 1995).

Accordingly, the effects of BAIBA on

peripheral tissues were abolished in

PPARa null mice or adipocytes and hepa-

tocytes pretreated with the selective

PPARa antagonist GW6471. Finally,

circulating BAIBA levels inversely corre-

lated with cardiometabolic risk factors in

humans. Thus this study elucidates an

additional mechanism that contributes to

the positive effects of exercise and shows

that BAIBA participates in tissue cross-

talk, being secreted by the contraction-

stimulated muscle and acting on liver

and fat tissues.

These findings raise several questions.

First, it would be interesting to measure

glucose uptake during a glucose chal-

lenge to quantify to what extent the

‘‘browning’’ of the subcutaneous adipose

tissue increases its glucose clearance

capacity, and whether this mechanism is

19, January 7, 2014 ª2014 Elsevier Inc. 1

Figure 1. BAIBA Mediates the Positive Effects of ExerciseBAIBA is released from the muscle after an exercise bout, promoting differentiation of brown adipocyte-like cells within subcutaneous fat depots and fat oxidation in the liver.

Cell Metabolism

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responsible for the improved glucose

tolerance profile. Second, the study did

not fully elucidate the mechanism by

which BAIBA acts on WAT and liver

(Figure 1). Consistent with the findings

described by Roberts et al. (2014), previ-

ous research has demonstrated that

BAIBA treatment prevents fat mass gain,

glucose intolerance, and hepatic steato-

sis in ob/+ mice fed a high-fat diet (Be-

griche et al., 2008). Intriguingly, the

same treatment in ob/ob mice fed a

normal chow diet did not lead to any of

these metabolic improvements, suggest-

2 Cell Metabolism 19, January 7, 2014 ª2014

ing that the effects of BAIBA are leptin

dependent. Indeed, ob/+ animals treated

with BAIBA had enhanced plasma leptin

levels (Begriche et al., 2008). It would be

interesting, therefore, to measure leptin

secretion in adipocytes treated with

BAIBA to understand if this effect is direct.

In conclusion, the current work under-

lines the importance of skeletal muscle

as an endocrine organ and provides

mechanistic insight into the positive

effects of exercise in disease prevention.

Furthermore, the current study confirms

that the adrenergic system does not

Elsevier Inc.

have a monopoly on BAT activation,

opening up new therapeutic possibilities

for treating metabolic diseases.

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