Nobiletin protects against insulin resistance and disorders of lipid metabolism by reprogramming of circadian clock in hepatocytes

• Published in: Biochimica et biophysica acta. Molecular and cell biology of lipids Vol. 1863; no. 6; pp. 549 - 562
• Main Authors: Qi, Guoyuan, Guo, Rui, Tian, Haoyu, Li, Lixia, Liu, Hua, Mi, Yashi, Liu, Xuebo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2018
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Bmal1; Circadian clock; Circadian Clocks - drug effects; Flavones - pharmacology; Glucose and lipid metabolism; Hep G2 Cells; Hepatocytes - cytology; Hepatocytes - metabolism; Humans; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Lipid Metabolism - drug effects; Nobiletin; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; IRS-1; HFD; Glucose and lipid metabolism; GSK-3; Cry; Clock; Bmal1; HDL; CREB; LDL; RT-PCR; NOB; GLUTs; T-CHO; IR; Circadian clock; PA; MMP; TG; Nobiletin; ROS; AMPK; Insulin resistance; Sirt1; Per; SCN
• ISSN: 1388-1981; 1879-2618; 1879-2618
• DOI: 10.1016/j.bbalip.2018.02.009

Circadian clock plays a principal role in orchestrating our daily physiology and metabolism, and their perturbation can evoke metabolic diseases such as fatty liver and insulin resistance. Nobiletin (NOB) has been demonstrated to possess antitumor and neuroprotective activities. The objective of the current study is to determine potential effects of NOB on modulating the core clock gene Bmal1 regarding ameliorating glucolipid metabolic disorders. Our results revealed that NOB partially reverse the relatively shallow daily oscillations of circadian clock genes and reset phase-shifting circadian rhythms in primary hepatocytes under metabolic disorders conditions. Importantly, NOB was found to be effective at amplifying glucose uptake via stimulating IRS-1/AKT signaling pathway, as well as blunting palmitate-induced lipogenesis in HepG2 cells via modulating AMPK-Sirt1 signaling pathway and key enzymes of de novo lipogenesis in a Bmal1-dependent manner. NOB attenuated palmitate-stimulated excessive secretions of ROS, restored the depletions of mitochondrial membrane potential, which is similar to the recovery in expressions of mitochondrial respiration complex I-IV. This study is the first to provide compelling evidences that NOB prevent cellular glucolipid metabolic imbalance and mitochondrial function in a Bmal1-dependent manner. Overall, NOB may serve as a nutritional preventive strategy in recovering metabolic disorders relevant to circadian clock. [Display omitted] •Nobiletin, as Bmal1-enhancing natural compounds, reverse the relatively shallow daily oscillations of circadian clock genes in primary hepatocytes metabolic disorders conditions.•Nobiletin amplify glucose uptake via stimulating IRS-1/AKT signaling pathway in Bmal1-dependent efficiency.•Bmal1 involved in nobiletin-stimulated AMPK-Sirt1 signaling pathway and expressions of key enzymes involved in de novo lipogenesis.