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P21-activated kinase-1 signaling is required to preserve adipose tissue homeostasis and cardiac function

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Abstract

While P21-activated kinase-1 (PAK1) has been extensively studied in relation to cardiovascular health and glucose metabolism, its roles within adipose tissue and cardiometabolic diseases are less understood. In this study, we explored the effects of PAK1 deletion on energy balance, adipose tissue homeostasis, and cardiac function utilizing a whole-body PAK1 knockout (PAK1−/−) mouse model. Our findings revealed that body weight differences between PAK1−/− and WT mice emerged at 9 weeks of age, with further increases observed at 12 weeks. Furthermore, PAK1−/− mice displayed increased fat mass and decreased lean mass at 12 weeks, indicating a shift towards adiposity. In conjunction with the increased body weight, PAK1−/− mice had increased food intake and reduced energy expenditure. At a mechanistic level, PAK1 deletion boosted the expression of lipogenic markers while diminishing thermogenic markers expression in adipose tissues, contributing to reduced energy expenditure and the overall obesogenic phenotype. Moreover, our findings highlighted a significant impact on cardiac function following PAK1 deletion, including alterations in calcium kinetics and compromised systolic and lusitropy functions. In summary, our study emphasizes the significant role of PAK1 in weight regulation and cardiac function, enriching our comprehension of heart health and metabolism. These findings could potentially facilitate the identification of novel therapeutic targets in cardiometabolic diseases.

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Data availability

Data generated for this study are available on request to the corresponding author.

Abbreviations

PAK1:

P21-activated kinase-1

PAK1− / − :

PAK1 global knock out mouse

gWAT:

Gonadal white adipose tissue

scWAT:

Subcutaneous white adipose tissue

iBAT:

Interscapular brown adipose tissue

NMVMs:

Neonatal mouse ventricular myocytes

UCP1:

Uncoupling protein 1

Dio2:

Type 2 iodothyronine deiodinase

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator

PRDM16:

PR domain containing 16

LPL:

Lipoprotein lipase

CPT1b:

Carnitine palmitoyl transferase 1b

PPARγ:

Peroxisome proliferator-activated receptor gamma

Ca2+ :

Intracellular calcium

PP2a:

Protein phosphatase 2a

PP1:

Protein phosphatase 1

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Funding

This work was supported by NIH/NHLBI K01HL155241 and AHA CDA849387 grants to PCR, and R01 DK132398 to YJ.

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Authors and Affiliations

  1. Divison of Endocrinology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Marcos Munoz

  2. Department of Health, Nutrition & Food Sciences, Florida State University, Tallahassee, FL, USA

    Christopher Solis

  3. Department of Ophthalmology & Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Maximilian McCann

  4. Department of Physiology & Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Jooman Park & Yuwei Jiang

  5. Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

    Koreena Rafael-Clyke, Shamim A. K. Chowdhury & Paola C. Rosas

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  1. Marcos Munoz
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  2. Christopher Solis
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  3. Maximilian McCann
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  4. Jooman Park
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  7. Yuwei Jiang
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Contributions

MM, CS, MMc, JP, KRC, SAKC and PCR performed experiments. MM, CS and PCR prepared and wrote the manuscript. MM and PCR were involved in experimental design, and data analysis. YJ was involved in manuscript editing.

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Correspondence to Paola C. Rosas.

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Munoz, M., Solis, C., McCann, M. et al. P21-activated kinase-1 signaling is required to preserve adipose tissue homeostasis and cardiac function. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04968-4

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