Clinical Application Potential of Small Molecules that Induce Brown Adipose Tissue Thermogenesis by Improving Fat Metabolism

Abstract

Mammalian fat comprises white and brown adipose tissue (WAT and BAT, respectively). WAT stores energy, whereas BAT is used for thermogenesis. In recent years, the incidence of obesity and its associated disorders have increased tremendously. Considering the thermogenic capacity and decreased levels of BAT with increasing age, BAT can be used as a suitable therapeutic target for the treatment of obesity and diabetes. In several studies, using positron emission tomography and computed tomography images, adult humans have been shown to have functional BAT in interscapular fat. Results of these basic research studies on BAT have shed light on the new components of transcriptional regulation and the role of hormones in stimulating BAT growth and differentiation. In this review article, we have summarized the thermogenic regulators identified in the past decades by focusing on peroxisome proliferator-activated receptor gamma/uncoupling protein 1 activators, branched-chain amino acids, fatty acids (lipokine), and adenosine monophosphate-activated protein kinase mediators. We have also presented the progress of a few ongoing clinical trials aimed at the treatment of obesity and its associated metabolic disorders. The main purpose of this review was to provide a comprehensive introduction to the latest knowledge of the representative thermogenic regulators for the treatment of obesity. The fat combustion capacity of BAT may have great potential and can be considered as a suitable target for the therapeutic application of drugs from bench-to-bed treatment of obesity and the associated diseases.

Keywords: AMP-activated protein kinase; brown adipose tissue; metabolism; thermogenesis.

Figure 1.

The accumulation of BCAAs in the blood vessels results in insulin resistance. BCAA catabolism in BAT enhances thermogenic activity because the upregulation of branched chain aminoacid amino-transferase and branched-chain alpha-keto acid dehydrogenase facilitate the oxidation. In the skeletal muscle, the utilization of BCAAs increases the glucose uptake and reduces the fatigue and muscle soreness. Increasing the clearance of BCAAs is a potential strategy for improving diabetes. BAT: brown adipose tissue; BCAA: branched-chain amino acid.

Figure 2.

HNF4-α expression regulates the release of acylcarnitine from the liver. Acylcarnitine acts as a fuel source for thermogenesis. PRDM16 expression regulates peroxisomes to induce the secretion of plasmalogens to communicate with the mitochondria. 12,13-diHOME promotes CD36/FATP1 translocation to the cell membrane to increase fatty acid uptake. Breast milk alkylglycerols regulate beige fat development via IL-6 and STAT3 signals. Lipokines are a critical fuel source for thermogenesis. 12,13-diHOME: 12,13-dihydroxy-9Z-octadecenoic acid; FATP1: fatty acid transport protein 1; HNF4-α: hepatocyte nuclear factor 4 alpha.

Figure 3.

Several small molecules induce SIRT1/PGC-1α/UCP1 to mediate thermogenesis. β-Lapachone phosphorylates AMPK/ACC/p38/JNK/ERK1/2, increases the mitochondrial count, and increases the antiobese and thermogenic effects. All the small molecules listed in Table 2 can improve insulin sensitivity and increase energy expenditure. ACC: acetyl-CoA carboxylase; AMPK: adenosine monophosphate-activated protein kinase.