NT-PGC-1α deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo

Kim, Jihyun; Park, Min Sung; Ha, Kyoung-Soo; Park, Chulhong; Lee, Jisu; Mynatt, Randall L.; Chang, Jason Y.

doi:10.1194/jlr.m085647

Cited by 13 publications

(9 citation statements)

References 40 publications

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“…We previously showed that NT-PGC-1α ablation decreases fatty acid oxidation in BAT 12 . Thus, we hypothesized that NT-PGC-1α −/− mice would be more prone to diet-induced obesity under high fat dietary conditions.…”

Section: Discussionmentioning

confidence: 93%

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NT-PGC-1α deficiency attenuates high-fat diet-induced obesity by modulating food intake, fecal fat excretion and intestinal fat absorption

Kim

Moon

Park

et al. 2021

Sci Rep

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Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α regulate metabolic adaptation by modulating many gene programs. Selective ablation of PGC-1α attenuates diet-induced obesity through enhancing fatty acid oxidation and thermogenesis by upregulation of NT-PGC-1α in brown adipose tissue (BAT). Recently, we have shown that selective ablation of NT-PGC-1α reduces fatty acid oxidation in BAT. Thus, the objective of this study was to test our hypothesis that NT-PGC-1α−/− mice would be more prone to diet-induced obesity. Male and female NT-PGC-1α+/+ (WT) and NT-PGC-1α−/− mice were fed a regular chow or 60% high-fat (HF) diet for 16 weeks. Contrary to our expectations, both male and female NT-PGC-1α−/− mice fed HFD were protected from diet-induced obesity, with more pronounced effects in females. This lean phenotype was primarily driven by reduced dietary fat intake. Intriguingly, HFD-fed female, but not male, NT-PGC-1α−/− mice further exhibited decreased feed efficiency, which was closely associated with increased fecal fat excretion and decreased uptake of fatty acids by the intestinal enterocytes and adipocytes with a concomitant decrease in fatty acid transporter gene expression. Collectively, our results highlight the role for NT-PGC-1α in regulating whole body lipid homeostasis under HFD conditions.

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Section: Discussionmentioning

confidence: 93%

“…The total number of animals used in this study was determined using the G*Power (v3.1.9.2) 40 with a power set at 80% and a significance level set at 0.05 for detecting a difference between two groups. NT-PGC-1α −/− mice have been described previously 12 . All mice were housed on a 12-h light/12-h dark cycle.…”

Section: Methodsmentioning

confidence: 99%

NT-PGC-1α deficiency attenuates high-fat diet-induced obesity by modulating food intake, fecal fat excretion and intestinal fat absorption

Kim

Moon

Park

et al. 2021

Sci Rep

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“…Locomotor activity and food intake over the 6-day period did not differ between the genotypes ( Supplementary Figures 1A , B ). It is well documented that CL316243-mediated activation of brown and beige adipose tissue upregulates genes involved in mitochondrial biogenesis, thermogenesis, mitochondrial electron transport activity, fatty acid oxidation, lipid metabolism, and glucose metabolism ( Yu et al, 2002 ; Chang et al, 2012 ; Mottillo et al, 2014 ; Hao et al, 2015 ; Kim et al, 2018 ). Thus, we examined the gene expression profiles of BAT and IWAT from Sgk2 +/+ and Sgk2 −/− mice treated with CL316243 for 10days.…”

Section: Resultsmentioning

confidence: 99%

Protein Kinase SGK2 Is Induced by the β3 Adrenergic Receptor-cAMP-PKA-PGC-1α/NT-PGC-1α Axis but Dispensable for Brown/Beige Adipose Tissue Thermogenesis

et al. 2021

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Brown and beige adipocytes are specialized to dissipate energy as heat. Sgk2, encoding a serine/threonine kinase, has been identified as a brown and beige adipocyte-specific gene in rodents and humans; however, its function in brown/beige adipocytes remains unraveled. Here, we examined the regulation and role of Sgk2 in brown/beige adipose tissue thermogenesis. We found that transcriptional coactivators PGC-1α and NT-PGC-1α activated by the β3 adrenergic receptor-cAMP-PKA pathway are recruited to the Sgk2 promoter, triggering Sgk2 transcription in response to cold. SGK2 elevation was closely associated with increased serine/threonine phosphorylation of proteins carrying the consensus RxRxxS/T phosphorylation site. However, despite cold-dependent activation of SGK2, mice lacking Sgk2 exhibited normal cold tolerance at 4°C. In addition, Sgk2+/+ and Sgk2−/− mice induced comparable increases in energy expenditure during pharmacological activation of brown and beige adipose tissue with a β3AR agonist. In vitro loss- and gain-of-function studies further demonstrated that Sgk2 ablation or activation does not alter thermogenic gene expression and mitochondrial respiration in brown adipocytes. Collectively, our results reveal a new signaling component SGK2, although dispensable for cold-induced thermogenesis that adds an additional layer of complexity to the β3AR signaling network in brown/beige adipose tissue.

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“…▶table 1 illustrates the effect of BAT activation via cold exposure and exercise on UCP1 and PGC-1α. In rodents, exposure to 4 °C increased UCP1 mRNA consistently after 3-24 h [17,[27][28][29][72][73][74][75][76][77][78][79][80], an effect that is maintained for up to 7 days [47,72,[81][82][83]. Chronic cold exposure for 4-5 weeks resulted in a new acclimation state characterized by elevated UCP1 content, demonstrating that cold exposure robustly increases UCP1 content in rodent BAT [47,84].…”

Section: Activation Of Ucp1mentioning

confidence: 99%

Is Exercise a Match for Cold Exposure? Common Molecular Framework for Adipose Tissue Browning

2020

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Exercise is commonly utilized for weight loss, yet research has focused less on specific modifications to adipose tissue metabolism. White adipose tissue (WAT) is the storage form of fat, whereas brown adipose tissue (BAT) is a thermogenic tissue whose uncoupling increases energy expenditure. The most established BAT activator is cold exposure, which also transforms WAT into “beige cells” that express uncoupling protein 1 (UCP1). Preliminary evidence in rodents suggests exercise elicits similar effects. The purpose of this review is to parallel and examine differences between exercise and cold exposure on BAT activation and beige induction. Like cold exposure, exercise stimulates the sympathetic nervous system and activates molecular pathways responsible for BAT/beige activation, including upregulation of BAT activation markers (UCP1, proliferator-activated receptor-gamma coactivator-1α) and stimulation of endocrine activators (fibroblast growth factor-21, irisin, and natriuretic peptides). Further, certain BAT activators are altered exclusively by exercise (interleukin-6, lactate). Markers of BAT activation increase from both cold exposure and exercise, whereas effects in WAT are compartment-specific. Stimulation of endocrine activators depends on numerous factors, including stimulus intensity and duration. Evidence of these analogous, albeit not mirrored, mechanisms is demonstrated by increases in adipose activity in rodents, while effects remain challenging to quantify in humans.

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NT-PGC-1α deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo

Cited by 13 publications

References 40 publications

NT-PGC-1α deficiency attenuates high-fat diet-induced obesity by modulating food intake, fecal fat excretion and intestinal fat absorption

NT-PGC-1α deficiency attenuates high-fat diet-induced obesity by modulating food intake, fecal fat excretion and intestinal fat absorption

Protein Kinase SGK2 Is Induced by the β3 Adrenergic Receptor-cAMP-PKA-PGC-1α/NT-PGC-1α Axis but Dispensable for Brown/Beige Adipose Tissue Thermogenesis

Is Exercise a Match for Cold Exposure? Common Molecular Framework for Adipose Tissue Browning

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