Docosahexaenoic Acid Inhibits White Adipogenesis and Enhances Mitochondrial Biogenesis through SIRT1 and Hh Signaling

Obesity has emerged as a worldwide phenomenon and leads to related diseases including cardiovascular diseases, type‐2 diabetes, and cancer. We previously demonstrated that docosahexaenoic acid (DHA), an ω‐3 fatty acids (PUFA) rich in fish oils known to reduce inflammation‐driven metabolic syndrome, inhibits forkhead box O1 expression in the liver and adipose tissues to reduce hepatic triglyceride synthesis. To further uncover the beneficial effects of DHA on adipocyte physiology related to adipogenesis and mitochondrial biogenesis, human adipose‐derived stem cells (hADSC) from subcutaneous fat depots were treated with different FA (saturated or unsaturated) during adipocyte differentiation. Strikingly, DHA‐treated hADSCs showed strong inhibition in white adipogenesis and increased characteristics of thermogenic beige adipocytes such as UCP1, PRDM16, TMEM26, and CD137 (browning of white fat). Mechanistically, this inhibition is resulted from activation of sirtuin 1 (SIRT1) and hedgehog (Hh) signaling. DHA also increased mitochondrial biogenesis in adipocytes through peroxisome proliferator‐activated receptor γ. Therefore, the renowned benefits of DHA on the amelioration of obesity‐ or inflammation‐ induced metabolic syndrome may be in part by the reduced adiposity of white adipose tissues and increased mitochondria biogenesis in mature beige adipocytes. Activation of SIRT1 or Hh signaling phenocopying effects of DHA could be potential therapeutics to treat metabolic diseases.