β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors

Abstract

Summary The transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-activator-1 α (PGC-1α) regulates metabolic genes in skeletal muscle, and contributes substantially to the response of muscle to exercise. Muscle specific PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolic profiling approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a novel small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipose tissue and fatty acid β-oxidation in hepatocytes both in vitro and in vivo through a PPARα mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.

A short bout of HFD promotes long-lasting hepatic lipid accumulation

“…Such notion is further supported by increased hepatic expression of enzymes involved in b-oxidation pointing toward increased hepatic respiratory capacity of HFD RF mice. 14 This may reflect an adaptation to increased lipid availability to protect from further accumulation of hepatic lipids. 15 But why do portal FFA levels remain increased 8 weeks after stopping short-term HFD?…”

Exercise regulation of adipose tissue

“…Three weeks of exercise training in mice by voluntary wheel-cage running and 20 wks of supervised submaximal aerobic exercise training (HERITAGE Family Study) in 80 human subjects resulted in a significant increase in circulating BAIBA. 42 Human pluripotent stem cells that were exposed to BAIBA while undergoing differentiation to mature white adipocytes had an increased expression of the beiging markers UCP1, CIDEA, and PRDM16. These data suggest that exercise in both mice and human subjects results in a significant increase in circulating BAIBA, and in rodents and isolated human cells, this increase may play a role in increased beiging of scWAT.…”

“…In addition, to lactate several other putative myokines that have been implicated in beiging include irisin, 27 meteorin-like 1, 40 myostatin, 41 and b-aminoisobutyric acid. 42 It has also been proposed that exercise training results in secretion of hypothalamic brain-derived neurotrophic factor (BDNF) that signals the beiging phenotype. 25 …”

“…42 BAIBA was identified as a potential myokine by LC-MS metabolic profiling of human myocytes that overexpressed PGC1a. Incubation of primary SVF cells isolated from mouse WAT with BAIBA, and addition of BAIBA to the drinking water of mice significantly increased expression of the beiging genes Ucp1 and Cidea.…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…Several recent reports demonstrate that elevating specific PGC-1α isoforms in skeletal muscle can impact other tissues by secreting circulating factors (myokines). Irisin and β-aminoisobutyric acid (BAIBA) [52,53], both under the control of PGC-1α1, or PGC-1α4-regulated myostatin and meteorin-like protein [54,55], all convey skeletal muscle signals to adipose tissue. Thus, skeletal muscle overexpression of either PGC-1α1 or PGC-1α4 results in browning of adipose tissue, although this is achieved through distinct pathways and mechanisms specific to each isoform.…”