bims-mimbat 2022-07-17 papers

FASEB J. 2022 Aug;36(8): e22461

Maternal L-carnitine supplementation promotes brown adipose tissue thermogenesis of newborn goats after cold exposure.

Xin Liu, Wenli Fan, Xujia Zhang, Siyuan Zhan, Tao Zhong, Jiazhong Guo, Yan Wang, Jiaxue Cao, Li Li, Hongping Zhang, Linjie Wang.

Brown adipose tissue (BAT) is an important component of energy expenditure and necessary to maintain body temperature for newborn mammals. In the previous study, we found that L-carnitine was enriched in BAT and promoted BAT adipogenesis and thermogenesis in goat brown adipocytes. However, whether dietary L-carnitine regulates BAT heat production and energy expenditure in lambs remains unclear. In this study, maternal L-carnitine supplementation elevated the rectal temperature, as well as the expression of UCP1 and mitochondrial DNA content to promote BAT thermogenesis in newborn goats. Moreover, maternal L-carnitine supplementation increased the levels of triglycerides (TG), non-esterified fatty acids (NEFA), and lactate in plasma, as well as the content of lipid droplet and glycogen in BAT of newborn goats. Lipidomic analysis showed that maternal L-carnitine supplementation remodeled the lipid composition of BAT in newborn goats. L-carnitine significantly increased the levels of TG and diglyceride (DG) and decreased the levels of glycerophospholipids and sphingolipids in BAT. Further studies showed that L-carnitine promoted TG and glycogen deposition in brown adipocytes through AMPKα. Our results indicate that maternal L-carnitine supplementation promotes BAT development and thermogenesis in newborn goats and provides new evidence for newborn goats to maintain body temperature in response to cold exposure.

Keywords: L-carnitine; brown adipose tissue; cold exposure; lipidomics; thermogenesis

DOI: https://doi.org/10.1096/fj.202200637R

Biochimie. 2022 Jul 08. pii: S0300-9084(22)00178-X. [Epub ahead of print]

Deletion of Letmd1 leads to the disruption of mitochondrial function in brown adipose tissue.

Runjie Song, Yaqi Du, Peng Li, Lijun Zhou, Han Zheng, Xiaohui Lu, Shenghong Wang, Wenqiang Ma, Hua Zhang, Xiangdong Li.

Human cervical cancer oncogene (HCCR-1), also named as LETMD1, is an LETM-domain containing outer mitochondrial membrane protein which plays an important role in carcinogenesis. The present study found that the loss of Letmd1 in mice led to severe abnormities, such as brown adipose tissue (BAT) whitening, impaired thermogenesis of both BAT and beige fat, cold intolerance, diet-induced obesity, glucose intolerance and insulin resistance. Mechanically, the deletion of Letmd1 in BAT caused decreased level of both mitochondrial and intracellular Ca2+. The reduced intracellular Ca2+ could suppress the fission of mitochondria and ultimately lead to the disruption of BAT thermogenesis by regulating mitochondrial structures and functions. This study indicates that LETMD1 played a crucial role in BAT thermogenesis and energy homeostasis through regulating mitochondrial structures and functions, which provides a novel insight into therapeutic target exploration from oncogenes for metabolic disorders.

Keywords: Insulin resistance; LETMD1; Mitochondrial; Obesity; Thermogenesis; brown adipose tissue

DOI: https://doi.org/10.1016/j.biochi.2022.07.002

Mol Metab. 2022 Jul 11. pii: S2212-8778(22)00113-2. [Epub ahead of print] 101544

Endothelial TrkA coordinates vascularization and innervation in thermogenic adipose tissue and can be targeted to control metabolism.

Alexes C Daquinag, Zhanguo Gao, Yongmei Yu, Mikhail G Kolonin.

OBJECTIVE: Brown adipogenesis and thermogenesis in brown and beige adipose tissue (AT) involve vascular remodeling and sympathetic neuronal guidance. Here, we investigated the molecular mechanism coordinating these processes.
METHODS: We used mouse models to identify the molecular target of a peptide CPATAERPC homing to the endothelium of brown and beige AT.
RESULTS: We demonstrate that CPATAERPC mimics nerve growth factor (NGF) and identify a low molecular weight isoform of NGF receptor, TrkA, as the CPATAERPC cell surface target. We show that the expression of truncated endothelial TrkA is selective for brown and subcutaneous AT. Analysis of mice with endothelium-specific TrkA knockout revealed the role of TrkA in neuro-vascular coordination supporting the thermogenic function of brown adipocytes. A hunter-killer peptide D-BAT, composed of CPATAERPC and a pro-apoptotic domain, induced cell death in the endothelium and adipocytes. This resulted in thermogenesis impairment, and predisposed mice to obesity and glucose intolerance. We also tested if this treatment can inhibit the tumor recruitment of lipids mobilized from adipocytes from adjacent AT. Indeed, in a mouse model of breast cancer D-BAT suppressed tumor-associated AT lipolysis, which resulted in reduced fatty acid utilization by cancer cells.
CONCLUSION: Our study demonstrates that TrkA signaling in the endothelium supports neuro-vascular coordination enabling beige adipogenesis.

Keywords: Brown adipose thermogenesis; Lipolysis; NGF; Neurovascular; Peptide; TrkA

DOI: https://doi.org/10.1016/j.molmet.2022.101544

Am J Physiol Endocrinol Metab. 2022 Jul 13.

Overexpressing hydroxycarboxylic acid receptor 1 in mouse brown adipose tissue restores glucose tolerance and insulin sensitivity in diet-induced obese mice.

Hyeon-Young Min, Jiyeon Hwang, Yuna Choi, Young-Hwan Jo.

Interscapular BAT (iBAT) plays an important role in the control of glucose homeostasis. Increased glucose entry and glycolysis in iBAT result in lactate production and release. The adipose tissue expresses the lactate receptor hydrocarboxylic acid receptor 1 (HCAR1) that is markedly downregulated in male diet-induced obese (DIO) and ob/ob mice. In this study, we examined the role of HCAR1 in iBAT in controlling glucose homeostasis in male DIO mice. We overexpressed HCAR1 in iBAT by injecting adeno-associated viruses (AAV) expressing HCAR1 into the iBAT pads of male DIO C57BL/6J mice. Overexpressing HCAR1 in iBAT resulted in augmented glucose uptake by iBAT in response to treatment with the HCAR1 agonist. HCAR1 overexpression elevated iBAT temperature associated with increased thermogenic gene expression in iBAT. HCAR1 overexpression prevented body weight gain in male DIO mice. Importantly, mice overexpressing HCAR1 in iBAT exhibited improved glucose tolerance and insulin sensitivity. HCAR1 overexpression upregulated the Slc2a4 gene expression and promoted GLUT4 trafficking to the plasma membrane. In addition, mice overexpressing HCAR1 displayed a decrease in HSL phosphorylation and increased lipogenic enzyme gene expression in iBAT. Unlike DIO mice, overexpressing HCAR1 in iBAT of mice fed a low-fat diet did not change body weight gain and glucose homeostasis. Taken together, our results support the interpretation that HCAR1 expressed in iBAT promotes glucose entry and reduces lipolysis in iBAT of male DIO mice. As activation of HCAR1 in iBAT restores body weight, glucose tolerance, and insulin sensitivity in male DIO mice, targeting HCAR1 in iBAT would provide an alternative way to control body weight and euglycemia in individuals with obesity.

Keywords: G protein; glucose; glycolysis; lactate; obesity

DOI: https://doi.org/10.1152/ajpendo.00084.2022

Chemphyschem. 2022 Jul 11.

Hydroxide Ion Mechanism for Long-Range Proton Pumping in the Third Proton Transfer of Bacteriorhodopsin.

Junichi Ono, Chika Okada, Hiromi Nakai.

In bacteriorhodopsin, representative light-driven proton pump, five proton transfers yield vectorial active proton translocation, resulting in a proton gradient in microbes. Third proton transfer occurs from Asp96 to the Schiff base on the photocycle, which is expected to be a long-range proton transfer via the Grotthuss mechanism through internal water molecules. Here, large-scale quantum molecular dynamics simulations are performed for the third proton transfer, where all the atoms (~50000 atoms) are treated quantum-mechanically. The simulations demonstrate that two reaction paths exist along the water wire, namely, via hydronium and via hydroxide ions. The free energy analysis confirms that the path via hydroxide ions is considerably favorable and consistent with the observed lifetime of the transient water wire. Therefore, the proposed hydroxide ion mechanism, as in the first proton transfer, is responsible for the third long-range proton transfer.

Keywords: Quantum Chemistry; Reaction mechanism; molecular dynamics; proteins; proton transport

DOI: https://doi.org/10.1002/cphc.202200109