Angiopoietin-like 4 governs diurnal lipoprotein lipase activity in brown adipose tissue

Eenige, Robin van; Panhuis, Wietse In Het; Schönke, Milena; Jouffe, Céline; Devilee, Thomas; Siebeler, Ricky; Streefland, Trea C M; Sips, Hetty C M; Pronk, Amanda; Vorderman, Ruben H P; Mei, Hailiang; Klinken, Jan B. van; Weeghel, Michel van; Uhlenhaut, Nina H; Kersten, Sander; Rensen, Patrick C.N.; Kooijman, Sander

doi:10.1016/j.molmet.2022.101497

Cited by 8 publications

(8 citation statements)

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“…We next assessed expression of Lpl and its negative regulator Angptl4 in BAT, as we have previously shown that these are crucial regulators of diurnal TG-derived FA uptake [ 17 , 24 ]. Lpl gene expression ( Figure 5A ) and LPL protein abundance ( Figure 5B ) were higher at ZT12 than ZT0 in young mice, in line with previous observations [ 17 , 24 ], but not in middle-aged mice. Angptl4 expression tended to be lower at ZT12 than ZT0 regardless of age ( Figure 5C ).…”

Section: Resultsmentioning

confidence: 99%

“…We anticipate that the de-regulation of these oscillations impairs cardiometabolic health [34,35]. Mechanistically, aging caused a time-age interaction, with a trend for lower LPL abundance at ZT12, a factor which we previously identified as crucial regulator of diurnal metabolic BAT activity [17,24] driven by rhythmic activity of glucocorticoids and possibly the sympathetic nervous system [14,36]. In the current study we did not find evidence for altered glucocorticoid levels or oscillations; an effect that is expected at higher age in C57BL/6J mice [37,38].…”

Section: Discussionmentioning

confidence: 99%

“…BAT displays pronounced diurnal variation in transcriptional activity, lipid content, and nutrient uptake [ 17 , 18 , 24 , 25 ], of which the latter highly contributes to the beneficial effects of BAT on cardiometabolic health [ 10 , 11 ]. While previous studies show an age-related dampening in oscillations of mRNA levels and lipid abundance in BAT [ 25 , 26 ], it is unknown how aging affects diurnal nutrient uptake by BAT.…”

Section: Discussionmentioning

confidence: 99%

“…In line with our observations that middle-aged mice show reduced Bmal1 expression, loss of Bmal1 in BAT has been shown to result in reduced beta oxidation and to promote whitening of BAT [ 43 ]. Given that nearly half of the transcriptome of BAT is oscillating with distinctive expression patterns [ 24 ], future studies should include more time points to delineate mechanisms underlying the age-related attenuation of diurnal metabolic BAT activity.…”

Section: Discussionmentioning

confidence: 99%

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Aging attenuates diurnal lipid uptake by brown adipose tissue

Panhuis

Schönke

Siebeler

et al. 2022

Aging

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Brown adipose tissue (BAT) contributes to cardiometabolic health by taking up glucose and lipids for oxidation, a process that displays a strong diurnal rhythm. While aging has been shown to reduce thermogenic characteristics of BAT, it is as yet unknown whether this reduction is specific to the time of day. Therefore, we assessed whole-body and BAT energy metabolism in young and middle-aged male and female C57BL/6J mice and studied the consequences for lipid metabolism in humanized APOE*3-Leiden.CETP mice (also on a C57BL/6J background). We demonstrate that in middle-aged versus young mice body temperature is lower in both male and female mice, while uptake of triglyceride (TG)-derived fatty acids (FAs) by BAT, reflecting metabolic activity, is attenuated at its peak at the onset of the dark (wakeful) phase in female mice. This coincided with delayed plasma clearance of TG-rich lipoproteins and TG-depleted lipoprotein core remnants, and elevated plasma TGs at the same time point. Furthermore, middle-aged female mice showed increased adiposity, accompanied by lipid accumulation, increased expression of genes involved in lipogenesis, and reduced expression of genes involved in fat oxidation and the intracellular clock machinery in BAT. Peak abundance of lipoprotein lipase (LPL), a crucial regulator of FA uptake, was attenuated in BAT. Our findings suggest that LPL is a potential therapeutic target for restoring diurnal metabolic BAT activity, and that efficiency of strategies targeting BAT may be improved by including time of day as an important factor.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Aging attenuates diurnal lipid uptake by brown adipose tissue

Panhuis

Schönke

Siebeler

et al. 2022

Aging

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“…25 In line with previous findings, 26 we observed that CD delayed the clearance of circulating lipids by reducing the uptake of TG-derived FA by BAT and WAT. Both BAT and WAT display pronounced diurnal variation in metabolic functioning [27][28][29] that is disturbed upon CD. 26,30 Interestingly, while both testosterone and estradiol have been linked to metabolic BAT activity, 31,32 depletion of gonadal sex hormones did not affect TG-derived FA uptake by BAT in our study.…”

Section: Discussionmentioning

confidence: 99%

Circadian disruption impairs glucose homeostasis in male but not in female mice and is dependent on gonadal sex hormones

et al. 2023

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Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6-h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropinreleasing hormone-antagonist degarelix. We demonstrate that CD has sex-specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG-rich lipoproteins in both sexes, coinciding with reduced TG-derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex-dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers.

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