Hypothalamic mitochondria in energy homeostasis and obesity

Obesity, which is largely due to energy imbalance, has emerged as one of the most serious health issues in the world. The hypothalamus is the most important organ to regulate feeding behavior and energy expenditure through nutrient sensing and signal integration from central and peripheral pathways. As the main organelle to produce energy, mitochondria play a critical role in energy homeostasis from the organelle level. Besides providing a platform for the oxidation of fuel substrates, mitochondria are also involved in a variety of cell signaling pathways and modulate energy homeostasis through mitochondrial dynamics. Mitochondrial dysfunction may lead to obesity due to inadequate ATP production, oxidative stress, endoplasmic reticulum stress, and inflammation. β, β-carotene-9’,10’-oxygenase2 (BCO2) is a mitochondrial enzyme that catalyzes the asymmetric cleavage of both provitamin A and non-provitamin A carotenoids. This enzyme is localized to the inner mitochondrial membrane, where the electron transport chain is located. Besides the enzymatic function, BCO2 is important for mitochondrial function and is genetically associated with interleukin-18. Moreover, BCO2 protein expression is suppressed in obese and diabetic mice. Given that the important role of BCO2 in mitochondrial structure and function, and the key position of the hypothalamus in energy balance, BCO2 may play a new role in maintaining metabolic homeostasis that has been overlooked before. The mutation of BCO2 might lead to the impairment of whole body energy homeostasis through hypothalamic mitochondrial dysfunction. Here we will be presenting the updates on hypothalamic mitochondria in cellular energy homeostasis and discussing the potential of BCO2 in regulation of hypothalamic mitochondria in health and obesity. Abbreviations: 4-PBA: 4-phenylbutyrate; ACS: acetyl-CoA synthetase; AgRP: agouti-related protein; AKT: protein kinase B; AMP: adenosine monophosphate; AMPK: adenosine monophosphateactivated protein kinase; ARC: arcuate nucleus; BAT: brown adipose tissue; BCO2: β, β-carotene-9’,10’-oxygenase2; BMP7: bone morphogenetic protein 7; CART: cocaineand amphetamineregulated transcript; CNS: central nervous system; DMH: dorsomedial hypothalamic nucleus; ER: endoplasmic reticulum; ETC: electron transport chain; FFA: free fatty acid; GLP-1: glucagon-like peptide-1; IKK: IκB kinaseβ; IKKβ: inhibitor of nuclear factor kappa-B kinase; InsR: insulin receptor; IRS: insulin receptor substance; JAK: Janus kinase; JNK: c-Jun N-terminal kinase; KATP: ATP-sensitive potassium; LCFA: long-chain fatty acid; LepR: leptin receptor; LHA: lateral hypothalamic area; MAMs: mitochondrial-associated membranes; MAPK: mitogenactivated protein kinase; MC4R: melanocortin 4 receptors; Mfn: mitofusins; mTOR: mammalian target of rapamycin; NF-κβ: nuclear factor kappa–B; NMDA: N-methyl-d-aspartate; NPY: neuropeptide Y; NRFs: nuclear respiratory factors; OXM: oxyntomodulin; OXPHOS: oxidative phosphorylation; PDK1: 3-phosphoinositide-dependent protein kinase 1; PGC: peroxisome proliferator-activated receptor gamma coactivator family; PI3K: phosphoinositide 3-kinase; PIP3: phosphatidylinositol 3,4,5-trisphosphate; PKCτ: protein kinase C iota; POMC: proopiomelanocortin; PRDM16: PR Domain Containing 16; PTP1B: protein tyrosine phosphatase 1B; PVN: paraventricular nucleus; ROS: reactive oxygen species; SOCS3: suppressor of cytokine signaling 3; SOD2: superoxide dismutase; STAT: signal transducers and activators of transcription; TCA: tricarboxylic acid; TGF-β: transforming growth factor beta; TLR4: toll-like receptor 4; TNFα: tumor necrosis factor alpha; TUDCA: tauroursodeoxycholic acid; UCP2: uncoupling protein 2; VMH: ventromedial hypothalamus; α-MSH: α-melanocyte stimulating hormone.