Protein Kinase D1 Deletion in Adipocytes Enhances Energy Dissipation and Protects Against Adiposity

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2018 Nov 4

PMID 30389661

Citations 16

Authors

Mona C Loffler

Alexander E Mayer

Jonathan Trujillo Viera

Angel Loza Valdes

Rabih El-Merahbi

Carsten P Ade

Till Karwen

Werner Schmitz

Anja Slotta

Manuela Erk

Sudha Janaki-Raman

Nuria Matesanz

Jorge L Torres

Miguel Marcos

Guadalupe Sabio

Martin Eilers

Almut Schulze

Grzegorz Sumara

Affiliations

Soon will be listed here.

Abstract

Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein-coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancer binding protein (C/EBP)-α- and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, depletion of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.

Citing Articles

Integrated analysis of muscle lncRNA and mRNA of Chinese indigenous breed Ningxiang pig in four developmental stages.

Chen W, Yang F, Liufu S, Li Z, Gong Y, Ma H Front Vet Sci. 2024; 11:1465389.

PMID: 39497745 PMC: 11533148. DOI: 10.3389/fvets.2024.1465389.

GCKIII kinases control hepatocellular lipid homeostasis via shared mode of action.

Cansby E, Caputo M, Andersson E, Saghaleyni R, Henricsson M, Xia Y J Lipid Res. 2024; 65(11):100669.

PMID: 39395791 PMC: 11602991. DOI: 10.1016/j.jlr.2024.100669.

Extracellular glucose and dysfunctional insulin receptor signaling independently upregulate arterial smooth muscle TMEM16A expression.

Raghavan S, Brishti M, Bernardelli A, Mata-Daboin A, Jaggar J, Leo M Am J Physiol Cell Physiol. 2024; 326(4):C1237-C1247.

PMID: 38581667 PMC: 11193522. DOI: 10.1152/ajpcell.00555.2023.

Platelet-derived lipids promote insulin secretion of pancreatic β cells.

Karwen T, Kolczynska-Matysiak K, Gross C, Loffler M, Friedrich M, Loza-Valdes A EMBO Mol Med. 2023; 15(9):e16858.

PMID: 37490001 PMC: 10493578. DOI: 10.15252/emmm.202216858.

Membrane trafficking in breast cancer progression: protein kinase D comes into play.

Gutierrez-Galindo E, Yilmaz Z, Hausser A Front Cell Dev Biol. 2023; 11:1173387.

PMID: 37293129 PMC: 10246754. DOI: 10.3389/fcell.2023.1173387.

References

Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y . Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun. 2014; 5:5493. DOI: 10.1038/ncomms6493. View

Fielitz J, Kim M, Shelton J, Qi X, Hill J, Richardson J . Requirement of protein kinase D1 for pathological cardiac remodeling. Proc Natl Acad Sci U S A. 2008; 105(8):3059-63. PMC: 2268584. DOI: 10.1073/pnas.0712265105. View

Cai K, El-Merahbi R, Loeffler M, Mayer A, Sumara G . Ndrg1 promotes adipocyte differentiation and sustains their function. Sci Rep. 2017; 7(1):7191. PMC: 5543145. DOI: 10.1038/s41598-017-07497-x. View

Dixon T, Daniel K, Farmer S, Collins S . CCAAT/enhancer-binding protein alpha is required for transcription of the beta 3-adrenergic receptor gene during adipogenesis. J Biol Chem. 2000; 276(1):722-8. DOI: 10.1074/jbc.M008440200. View

Bijland S, Mancini S, Salt I . Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin Sci (Lond). 2013; 124(8):491-507. DOI: 10.1042/CS20120536. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Kim M, Fielitz J, McAnally J, Shelton J, Lemon D, McKinsey T . Protein kinase D1 stimulates MEF2 activity in skeletal muscle and enhances muscle performance. Mol Cell Biol. 2008; 28(11):3600-9. PMC: 2423294. DOI: 10.1128/MCB.00189-08. View

Sumara G, Sumara O, Kim J, Karsenty G . Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab. 2012; 16(5):588-600. PMC: 3696514. DOI: 10.1016/j.cmet.2012.09.014. View

Dirkx E, van Eys G, Schwenk R, Steinbusch L, Hoebers N, Coumans W . Protein kinase-D1 overexpression prevents lipid-induced cardiac insulin resistance. J Mol Cell Cardiol. 2014; 76:208-17. DOI: 10.1016/j.yjmcc.2014.08.017. View

10.

Ittner A, Block H, Reichel C, Varjosalo M, Gehart H, Sumara G . Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung. J Exp Med. 2012; 209(12):2229-46. PMC: 3501357. DOI: 10.1084/jem.20120677. View

11.

Sumara G, Formentini I, Collins S, Sumara I, Windak R, Bodenmiller B . Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell. 2009; 136(2):235-48. PMC: 2638021. DOI: 10.1016/j.cell.2008.11.018. View

12.

Gaidhu M, Frontini A, Hung S, Pistor K, Cinti S, Ceddia R . Chronic AMP-kinase activation with AICAR reduces adiposity by remodeling adipocyte metabolism and increasing leptin sensitivity. J Lipid Res. 2011; 52(9):1702-11. PMC: 3151690. DOI: 10.1194/jlr.M015354. View

13.

Coughlan K, Valentine R, Sudit B, Allen K, Dagon Y, Kahn B . PKD1 Inhibits AMPKα2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in Skeletal Muscle Cells. J Biol Chem. 2016; 291(11):5664-5675. PMC: 4786706. DOI: 10.1074/jbc.M115.696849. View

14.

Rossmeisl M, Barbatelli G, Flachs P, Brauner P, Zingaretti M, Marelli M . Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo. Eur J Biochem. 2002; 269(1):19-28. DOI: 10.1046/j.0014-2956.2002.02627.x. View

15.

Rohm M, Schafer M, Laurent V, Ekim Ustunel B, Niopek K, Algire C . An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat Med. 2016; 22(10):1120-1130. DOI: 10.1038/nm.4171. View

16.

El-Merahbi R, Loffler M, Mayer A, Sumara G . The roles of peripheral serotonin in metabolic homeostasis. FEBS Lett. 2015; 589(15):1728-34. DOI: 10.1016/j.febslet.2015.05.054. View

17.

Twig G, Hyde B, Shirihai O . Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta. 2008; 1777(9):1092-7. PMC: 3809017. DOI: 10.1016/j.bbabio.2008.05.001. View

18.

Spiegelman B, Flier J . Obesity and the regulation of energy balance. Cell. 2001; 104(4):531-43. DOI: 10.1016/s0092-8674(01)00240-9. View

19.

Zechner R, Zimmermann R, Eichmann T, Kohlwein S, Haemmerle G, Lass A . FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012; 15(3):279-91. PMC: 3314979. DOI: 10.1016/j.cmet.2011.12.018. View

20.

Zhu Q, Ghoshal S, Rodrigues A, Gao S, Asterian A, Kamenecka T . Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis. J Clin Invest. 2016; 126(11):4273-4288. PMC: 5096898. DOI: 10.1172/JCI85510. View