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The International Journal of... May 2010Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs, is a unique function of white adipose... (Review)
Review
Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs, is a unique function of white adipose tissue. Lipolysis in adipocytes occurs at the surface of cytosolic lipid droplets, which have recently gained much attention as dynamic organelles integral to lipid metabolism. Desnutrin/ATGL is now established as a bona fide TAG hydrolase and mutations in human desnutrin/ATGL/PNPLA2, as well as in its activator, comparative gene identification 58, are associated with Neutral Lipid Storage Disease. Furthermore, recent identification of AdPLA as the major adipose phospholipase A(2), has led to the discovery of a dominant autocrine/paracrine regulation of lipolysis through PGE(2). Here, we review emerging concepts in the key players in lipolysis and the regulation of this process. We also examine recent findings in mouse models and humans with alterations/mutations in genes involved in lipolysis and discuss activation of lipolysis in adipocytes as a potential therapeutic target.
Topics: Adipocytes, White; Animals; Humans; Lipidoses; Lipolysis; Myopathies, Structural, Congenital; Obesity; Organelles
PubMed: 20025992
DOI: 10.1016/j.biocel.2009.12.009 -
Lipids in Health and Disease Jun 2017Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles... (Review)
Review
Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles found in almost all organisms, from bacteria to mammals. They are composed of a hydrophobic neutral lipid core surrounding by a phospholipid monolayer membrane with various decorating proteins. Degradation of LDs provide metabolic energy for divergent cellular processes such as membrane synthesis and molecular signaling. Lipolysis and autophagy are two main catabolic pathways of LDs, which regulate lipid metabolism and, thereby, closely engaged in many pathological conditons. In this review, we first provide an overview of the current knowledge on the structural properties and the biogenesis of LDs. We further focus on the recent findings of their catabolic mechanism by lipolysis and autophagy as well as their connection ragarding the regulation and function. Moreover, we discuss the relevance of LDs and their catabolism-dependent pathophysiological conditions.
Topics: Animals; Autophagy; Humans; Lipid Droplets; Lipid Metabolism; Lipolysis; Phospholipids
PubMed: 28662670
DOI: 10.1186/s12944-017-0521-7 -
International Journal of Biological... 2023BAP31 expression was robustly decreased in obese white adipose tissue (WAT). To investigate the roles of BAP31 in lipid metabolism, adipocyte-specific conditional...
BAP31 expression was robustly decreased in obese white adipose tissue (WAT). To investigate the roles of BAP31 in lipid metabolism, adipocyte-specific conditional knockout mice (BAP31-ASKO) were generated. BAP31-ASKO mice grow normally as controls, but exhibited reduced lipid accumulation in WAT. Histomorphometric analysis reported increased adipocyte size in BAP31-ASKO mice. Mouse embryonic fibroblasts (MEFs) were induced to differentiation to adipocytes, showed reduced induction of adipogenic markers and attenuated adipogenesis in BAP31-deficient MEFs. BAP31-deficiency inhibited fasting-induced PKA signaling activation and the fasting response. β3-adrenergic receptor agonist-induced lipolysis also was reduced, accompanied by reduced free-fatty acids and glycerol release, and impaired agonist-induced lipolysis from primary adipocytes and adipose explants. BAP31 interacts with Perilipin1 via C-terminal cytoplasmic portion on lipid droplets (LDs) surface. Depletion of BAP31 repressed Perilipin1 proteasomal degradation, enhanced Perilipin1 expression and blocked LDs degradation, which promoted LDs abnormal growth and supersized LDs formation, resulted in adipocyte expansion, thus impaired insulin signaling and aggravated pro-inflammation in WAT. BAP31-deficiency increased phosphatidylcholine/phosphatidylethanolamine ratio, long chain triglycerides and most phospholipids contents. Overall, BAP31-deficiency inhibited adipogenesis and lipid accumulation in WAT, decreased LDs degradation and promoted LDs abnormal growth, pointing the critical roles in modulating LDs dynamics and homeostasis via proteasomal degradation system in adipocytes.
Topics: Animals; Mice; Adipogenesis; Fibroblasts; Lipid Droplets; Lipolysis; Obesity; Triglycerides; Perilipin-1
PubMed: 37063427
DOI: 10.7150/ijbs.82178 -
Physiological Reports Apr 2017Adipose tissue is increasingly being recognized as a key regulator of whole body carbohydrate and lipid metabolism. In conditions of obesity and insulin resistance... (Review)
Review
Adipose tissue is increasingly being recognized as a key regulator of whole body carbohydrate and lipid metabolism. In conditions of obesity and insulin resistance mitochondrial content in this tissue is reduced, while treatment with insulin sensitizing drugs such as thiazolidinediones (TZDs) increase mitochondrial content. It has been known for decades that exercise increases mitochondrial content in skeletal muscle and now several laboratories have shown similar effects in adipose tissue. To date the specific mechanisms mediating this effect have not been fully identified. In this review we highlight recent work suggesting that increases in lipolysis and subsequently fatty acid re-esterification trigger the activation of 5' AMP-activated protein kinase (AMP) activated protein kinase and ultimately the induction of mitochondrial biogenesis. It is our current view that this pathway could be a unifying mechanism linking numerous systemic factors (catecholamines, interleukin-6, meteorin-like) to induction of mitochondrial biogenesis following exercise.
Topics: Adipose Tissue; Animals; Exercise; Humans; Lipolysis; Organelle Biogenesis; Signal Transduction
PubMed: 28404813
DOI: 10.14814/phy2.13247 -
Trends in Endocrinology and Metabolism:... Oct 2016The selective breakdown by autophagy of lipid droplet (LD)-stored lipids, termed lipophagy, is a lysosomal lipolytic pathway that complements the actions of cytosolic... (Review)
Review
The selective breakdown by autophagy of lipid droplet (LD)-stored lipids, termed lipophagy, is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. The physiological importance of lipophagy has been demonstrated in multiple mammalian cell types, as well as in lower organisms, and this pathway has many functions in addition to supplying free fatty acids to maintain cellular energy stores. Recent studies have begun to delineate the molecular mechanisms of the selective recognition of LDs by the autophagic machinery, as well as the intricate crosstalk between the different forms of autophagy and neutral lipases. These studies have led to increased interest in the role of lipophagy in both human disease pathogenesis and therapy.
Topics: Animals; Autophagy; Humans; Lipid Droplets; Lipid Metabolism; Lipolysis; Perilipin-1
PubMed: 27365163
DOI: 10.1016/j.tem.2016.06.003 -
Current Opinion in Pharmacology Dec 2022Metabolism consists of life-sustaining chemical reactions involving metabolites. Historically, metabolites were defined as the intermediates or end products of... (Review)
Review
Metabolism consists of life-sustaining chemical reactions involving metabolites. Historically, metabolites were defined as the intermediates or end products of metabolism and considered to be passive participants changed by metabolic processes. However, recent research has redefined how we view metabolism. There is emerging evidence of metabolites which function to mediate cellular signalling and interorgan crosstalk, regulating local metabolism and systemic physiology. These bioactive metabolite signals have been termed metabokines. Metabokines regulate diverse energy metabolism pathways across multiple tissues, including fatty acid β-oxidation, mitochondrial oxidative phosphorylation, lipolysis, glycolysis and gluconeogenesis. There is increasing impetus to uncover novel metabokine signalling axes to better understand how these may be perturbed in metabolic diseases and determine their utility as therapeutic targets.
Topics: Humans; Energy Metabolism; Glycolysis; Lipolysis; Mitochondria
PubMed: 36137304
DOI: 10.1016/j.coph.2022.102286 -
Advanced Science (Weinheim,... Oct 2023White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert...
White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte β adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N -methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.
Topics: Animals; Mice; Adrenergic Agents; Insulin Resistance; Lipolysis; Methyltransferases; Non-alcoholic Fatty Liver Disease; Obesity; RNA
PubMed: 37526326
DOI: 10.1002/advs.202301645 -
Hepatology Communications Mar 2023Adipose tissue thermogenic activities use fatty acids from lipolysis for heat generation. Therefore, a tight coupling between lipolysis and thermogenesis is...
BACKGROUND
Adipose tissue thermogenic activities use fatty acids from lipolysis for heat generation. Therefore, a tight coupling between lipolysis and thermogenesis is physiologically imperative in maintaining not only body temperature but also lipids homeostasis. Adipose tissue dysfunction contributes to alcoholic liver disease (ALD). Here, studies were conducted to examine how alcohol intake affects adipose tissue thermogenic activities and whether altered adipose tissue thermogenesis contributes to ALD.
METHODS
Both the Lieber-DeCarli and the NIAAA mouse models of ALD were used. Denervation surgery in epididymal fat pads was performed. CL316,243, a selective β3-adrenoceptor agonist, SR59230A, a selective β3 adrenoceptor (ADRB3) antagonist, and rapamycin, a selective mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, were administrated through i.p. injection. Adipocyte-specific Prdm16 knockout mice were subjected to alcohol-containing diet chronically.
RESULTS
Chronic alcohol consumption, which enhances adipose tissue lipolysis, inhibits thermogenic activities of beige adipocytes in inguinal white adipose tissue (WAT), leading to an uncoupling status between lipolysis and thermogenesis in WAT at both basal and ADRB3 stimulation states. CL316,243 administration exacerbates liver pathologies of ALD. Alcohol intake inhibits mTORC1 activities in WAT. In mice, mTORC1 inhibition by rapamycin inhibits the thermogenesis of iWAT, whereas enhancing WAT lipolysis. Further investigations using adipocyte-specific Prdm16 knockout mice revealed that functional deficiency of beige adipocytes aggravates liver pathologies of ALD, suggesting that the inhibitory effect of alcohol on WAT browning/thermogenesis contributes to ALD pathogenesis.
CONCLUSION
Chronic alcohol consumption induces an "uncoupling status" between lipolysis and browning/thermogenesis in WAT by inhibiting mTORC1 activation. Diminished WAT browning/thermogenesis, concomitant with enhanced lipolysis, contributes to ALD pathogenesis.
Topics: Mice; Animals; Lipolysis; Adipose Tissue, Brown; Mechanistic Target of Rapamycin Complex 1; Adipose Tissue, White; Thermogenesis; Liver Diseases, Alcoholic; Mice, Knockout; Receptors, Adrenergic
PubMed: 36757400
DOI: 10.1097/HC9.0000000000000059 -
Molecular Metabolism May 2023Emerging evidence suggest the existence of constant basal lipolysis and re-esterification of a substantial fraction of thus liberated fatty acids. In stimulated...
OBJECTIVE
Emerging evidence suggest the existence of constant basal lipolysis and re-esterification of a substantial fraction of thus liberated fatty acids. In stimulated lipolysis, the re-esterification is proposed to be a protective mechanism against lipotoxicity; however, the role of the lipolysis coupled to re-esterification under basal conditions has not been deciphered.
METHODS
We used adipocytes (in vitro differentiated brown and white adipocytes derived from a cell line or primary SVF culture) to study the effect of inhibition of re-esterification by pharmacological DGAT1 and DGAT2 inhibitors alone or in combination. We then evaluated cellular energetics, lipolysis flux, and lipidomic parameters along with mitochondrial properties and fuel utilization.
RESULTS
In adipocytes, DGAT1 and 2 mediated re-esterification is a moderator of fatty acid oxidation. Combined inhibition of both DGATs (D1+2i) increases oxygen consumption, which is largely due to enhanced mitochondrial respiration by lipolysis-derived fatty acids (FAs). Acute D1+2i selectively affects mitochondrial respiration without affecting the transcriptional homeostasis of genes relevant to mitochondrial health and lipid metabolism. D1+2i enhances the mitochondrial import of pyruvate and activates AMP Kinase to counteract CPT1 antagonism, thus facilitating the mitochondrial import of fatty acyl-CoA.
CONCLUSIONS
These data implicate the process of re-esterification in the regulation of mitochondrial FA usage and uncover a mechanism of FAO regulation via crosstalk with FA re-esterification.
Topics: Fatty Acids; Esterification; Lipid Metabolism; Lipolysis; Adipocytes, White
PubMed: 36878315
DOI: 10.1016/j.molmet.2023.101701 -
Biochimica Et Biophysica Acta.... May 2022Adipose tissue is a critical organ for nutrient sensing, energy storage and maintaining metabolic health. The failure of adipose tissue homeostasis leads to metabolic... (Review)
Review
Adipose tissue is a critical organ for nutrient sensing, energy storage and maintaining metabolic health. The failure of adipose tissue homeostasis leads to metabolic disease that is seen during obesity or aging. Local metabolic processes are coordinated by interacting microenvironments that make up the complexity and heterogeneity of the adipose tissue. Catecholamine-induced lipolysis, a critical pathway in adipocytes that drives the release of stored triglyceride as free fatty acid after stimulation, is impaired during aging. The impairment of this pathway is associated with a failure to maintain a healthy body weight, core body-temperature during cold stress or mount an immune response. Along with impairments in aged adipocytes, aging is associated with an accumulation of inflammation, immune cell activation, and increased dysfunction in the nervous and lymphatic systems within the adipose tissue. Together these microenvironments support the initiation of stimulated lipolysis and the transport of free fatty acid under conditions of metabolic homeostasis. However, during aging, the defects in these cellular systems result in a reduction in ability to stimulate lipolysis. This review will focus on how the immune, nervous and lymphatic systems interact during tissue homeostasis, review areas that are impaired with aging and discuss areas of research that are currently unclear.
Topics: Adipocytes; Adipose Tissue; Fatty Acids, Nonesterified; Lipolysis
PubMed: 35131468
DOI: 10.1016/j.bbalip.2022.159118