The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation

Wang, Qiuyu; Sharma, Vishal; Shen, Hong; Xiao, Y.; Zhu, Qi; Xiong, Xuelian; Guo, Liang; Jiang, Lin; Ohta, Kunimasa; Li, Siming; Shi, Haifei; Rui, Liangyou; Lin, Jiandie D.

doi:10.1038/s42255-018-0020-9

Cited by 55 publications

(83 citation statements)

References 52 publications

(47 reference statements)

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“…Hepatic TSK expression and plasma TSK levels were elevated in obese patients. In mice, TSK deficiency augmented sympathetic innervation and norepinephrine release in adipose tissue, ending up in an amplification of adrenergic signalling and thermogenesis, a modest reduction in brown fat whitening, and the related maintenance of diet-induced obesity [28].…”

Section: Environmental Factorsmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy

Tarantino

Citro

Capone

2019

JCM

114

108

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Focusing on previously published mechanisms of non-alcoholic fatty liver disease (NAFLD), their uncertainty does not always permit a clear elucidation of the grassroot alterations that are at the basis of the wide-spread illness, and thus curing it is still a challenge. There is somehow exceptional progress, but many controversies persist in NAFLD research and clinical investigation. It is likely that hidden mechanisms will be brought to light in the near future. Hereby, the authors present, with some criticism, classical mechanisms that stand at the basis of NAFLD, and consider contextually different emerging processes. Without ascertaining these complex interactions, investigators have a long way left ahead before finding an effective therapy for NAFLD beyond diet and exercise. few are conclusively accepted by experts. We try to provide evidence of the complexity, and for some aspects the contradictions, of the main lines of basic and clinical research addressing this topic. The Role of Reactive Oxygen Species (ROS) OverproductionMalnutrition splits in two directions; undernutrition and overnutrition; both of them leading to severe health complications: Famine and overweight/obesity are the result of calorie deficit or excess, and both of them are major health problems. Constantly eating excess calories leads body fat stores to expand. One of the most active and productive hypotheses about the mechanisms inducing or worsening obesity and consequently NAFLD is the over-production of reactive oxygen species (ROS). Oxidative stress accompanying obesity is reckoned to be a key factor in the development of insulin resistance (IR), [4]. In fact, obese mice treated with NADPH oxidase inhibitors (reducing ROS) have clearly demonstrated the involvement of ROS in the genesis of IR, hepatic steatosis, and T2DM [5]. Mitochondria are clearly considered to be main contributors to oxidative stress in obesity induced by chronic over-nutrition, with subsequent reduced insulin sensitivity or IR [6]. The trigger that causes the oxidative stress in obesity is the energy surplus that eventually generates reducing equivalents. These exceed the rate of ATP utilization, giving space to the over-production of O 2 , and consequently reducing the redox-buffering capacity [7]. The aforementioned pathway has been fully highlighted in mice, characterized by deletion of manganese superoxide dismutase at the adipocyte level through enhanced mitochondrial biogenesis, mediated by uncoupling protein 1 [8].

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Section: Environmental Factorsmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy

Tarantino

Citro

Capone

2019

JCM

114

108

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“…Genes of cluster 1 were induced by light in WT cells, and their expression levels were elevated in Opn3-KO cells relative to WT cells, regardless of light or dark condition. Representatives of this cluster included Tsukushi (Tsku), which is a recently identified hepatokine that can regulate BAT energy expenditure [32], and Stearoyl-Coenzyme A Desaturase 2 (Scd2), which is required for PPARg expression in 3T3-L1 adipose cells [33]. Clusters 2 and 5 included genes that displayed opposite responses to light stimulation between WT and Opn3-KO cells.…”

Section: Identification Of Opn3-mediated and Light-sensitive Genes Bymentioning

confidence: 99%

Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes

et al. 2020

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Opsin3 (Opn3) is a transmembrane heptahelical G protein-coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin resistance. At the cellular level, Opn3-KO brown adipocytes cultured in darkness had decreased glucose uptake and lower nutrient-induced mitochondrial respiration than wild-type (WT) cells. Light exposure promoted mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3's putative G protein-binding domain also exhibited a reduction in glucose uptake and mitochondrial respiration in darkness. Using RNA-sequencing, we identified several novel light-sensitive and Opn3-dependent molecular signatures in brown adipocytes. Importantly, direct exposure of brown adipose tissue (BAT) to light in living mice significantly enhanced thermogenic capacity of BAT, and this effect was diminished in Opn3-KO animals. These results uncover a previously unrecognized cell-autonomous, light-sensing mechanism in brown adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and mitochondrial respiration. Our work also provides a molecular basis for developing light-based treatments for obesity and its related metabolic disorders. OPEN ACCESS Citation: Sato M, Tsuji T, Yang K, Ren X, Dreyfuss JM, Huang TL, et al. (2020) Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes. PLoS Biol 18(2): e3000630.

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“…Hepatocytes and NPCs release an array of secreted factors that exert diverse biological effects in the liver and beyond. As such, several hepatokines have emerged as important regulators of nutrient metabolism and energy balance by acting on the central nervous system and other peripheral tissues . Despite the expanding role of intercellular signaling in metabolic physiology and tissue homeostasis, a comprehensive survey of ligand and receptor gene expression and the landscape of intercellular crosstalk in the liver have not been fully elucidated.…”

Section: Landscape Of Intercellular Crosstalk Among Liver Cell Typesmentioning

confidence: 99%

“…As such, several hepatokines have emerged as important regulators of nutrient metabolism and energy balance by acting on the central nervous system and other peripheral tissues. (13,14) Despite the expanding role of intercellular signaling in metabolic physiology and tissue homeostasis, a comprehensive survey of ligand and receptor gene expression and the landscape of intercellular crosstalk in the liver have not been fully elucidated. Xiong et al performed single-cell secretome gene analysis on NPCs and hepatocytes isolated from mouse liver.…”

Section: Landscape Of Intercellular Crosstalk Among Liver Cell Typesmentioning

confidence: 99%