Local hyperthermia therapy induces browning of white fat and treats obesity

Yu, Longquan; Wang, Dongmei; Ping, Xiaodan; Zhang, Yankang; Zhang, Ting; Wang, Li; Jin, Li; Zhao, Wenjun; Guo, Mingwei; Shen, Fei; Meng, Meiyao; Chen, Xin; Zheng, Ying; Wang, Jiqiu; Li, Dali; Zhang, Qiang; Hu, Cheng; Xu, Lingyan; Ma, Xinran

doi:10.1016/j.cell.2022.02.004

Cited by 88 publications

(48 citation statements)

References 104 publications

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“…This brings up the possibility that the observed effects of fedratinib on thermogenic activation might be due to inhibition of an activated tyrosine kinase, especially in view that JAK2 KO mice were unable to upregulate BAT UCP1 following a high-fat diet or after cold exposure [42]. However, involvement of JAK2 in BAT regulation could be demonstrated only in the presence of non-adipocyte tissue cells (which is not the case in our ex vivo differentiated adipocytes) and it was dispensable for induction of UCP1 thermogenesis in WAT through beige adipocytes which are presumed to be dominant among DN adipocytes [7-10, 12, 43]. Nevertheless, we carried out all of our critical experiments applying the competitive ThTr inhibitor amprolium as well and found that the inhibition of thermogenic response by amprolium was comparable to the fedratinib effect.…”

Section: Discussionmentioning

confidence: 99%

Availability of abundant thiamine determines efficiency of thermogenic activation in human neck area derived adipocytes

Arianti

Vinnai

Győry

et al. 2022

Preprint

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Objective: Brown/beige adipocytes are characterized by expression of uncoupling protein-1 (UCP1) that enables them to dissipate energy as heat instead of generating ATP. The activation of this process can alleviate obesity as it augments energy expenditure. Human brown adipose tissue is interspersed in distinct anatomical regions including the deep neck area. We found that UCP1 enriched adipocytes differentiated from progenitors of this depot highly expressed ThTr2 transporter of thiamine, the precursor of thiamine pyrophosphate (TPP) cofactor for mitochondrial fuel generating enzymes, and aimed to investigate the importance of thiamine availability during thermogenic activation. Methods: Human adipocytes were differentiated from subcutaneous and deep neck precursors and activated for thermogenesis by the cell permeable dibutyryl-cAMP, which mimics adrenergic stimulation. Proton leak respiration reflecting heat generation was monitored by Seahorse XF analyzer. Direct mitochondrial effect of TPP was observed in flux assay of permeabilized adipocytes. Expression of thermogenic genes and proteins was analyzed by RT-qPCR and immunoblotting, respectively. Results: Inhibition of ThTr2 during thermogenic activation of deep and subcutaneous neck derived adipocytes by cAMP led to decreased proton leak respiration reflecting lower uncoupling activity. In the absence of thiamine, cAMP-induced elevation of proton leak respiration was diminished but restored by thiamine addition reaching highest levels in deep neck adipocytes and at concentrations larger than present in human blood plasma. Addition of TPP to permeabilized adipocytes increased proton leak respiration fueled by one of the TPP-dependent enzymes, pyruvate dehydrogenase. ThTr2 inhibition also hampered cAMP-dependent induction of UCP1, PGC1a and other browning marker genes, along with mitochondrial complex subunits, and thermogenic induction of these genes was potentiated by thiamine in a concentration dependent manner. Conclusion: Our study has revealed the importance of amply supplied thiamine during thermogenic activation in human adipocytes. Thiamine may increase heat generation by providing TPP for TPP-dependent enzymes which lack this cofactor and by potentiating the induction of UCP1 and other thermogenic genes.

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Section: Discussionmentioning

confidence: 99%

Availability of abundant thiamine determines efficiency of thermogenic activation in human neck area derived adipocytes

Arianti

Vinnai

Győry

et al. 2022

Preprint

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“…But this inverse relation may also be because greater levels of WAT confer better cold resistance due to its insulative properties ( Speakman, 2018 ) and hence lower the need for thermogenesis derived from BAT. Nevertheless, the potential to stimulate BAT, or force the conversion of beige adipocytes from their white to brown form, has received enormous attention, particularly in studies of mice ( Li et al., 2022 ; Nedergaard and Cannon, 2014 ; Rosenwald et al., 2013 ; Wang et al., 2016 ). This has been stimulated in part by observations that transplanting BAT but not WAT in mice causes weight loss and can reverse diet-induced or genetic obesity ( Liu et al., 2013 , 2015 ; Stanford and Goodyear, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Human total, basal and activity energy expenditures are independent of ambient environmental temperature

Zhang¹,

Yamada²,

Sagayama³

et al. 2022

iScience

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“…These results are consistent with the pattern of rectal temperature changes in newborn goats in the present study. However, the body temperature was decreased after cold exposure, while enhancing BAT thermogenesis to keep body temperature constant in mice 31–33 . We speculated that it is a difference in thermoregulation between large animals and mice after acute cold exposure.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2022

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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.

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Local hyperthermia therapy induces browning of white fat and treats obesity

Cited by 88 publications

References 104 publications

Availability of abundant thiamine determines efficiency of thermogenic activation in human neck area derived adipocytes

Availability of abundant thiamine determines efficiency of thermogenic activation in human neck area derived adipocytes

Human total, basal and activity energy expenditures are independent of ambient environmental temperature

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

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