The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation.
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ABSTRACT:
SUBMITTER: El-Merahbi R
PROVIDER: S-EPMC7111262 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Beta-adrenergic stimulation stabilizes ERK3, resulting in the formation of a complex with MK5 and thereby driving lipolysis. A downstream target of the complex is FOXO1, which controls expression of the lipolytic enzyme ATGL. Deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation.
2021-01-01 | GSE142424 | GEO
Project description:Adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation
| PRJNA597001 | ENA
Project description:Psychological stress activates the autonomic nervous system to protect organisms through an integrated response involving changes to both behavior and metabolism. Epinephrine is an important driver of this response, activating adipose tissue lipolysis3and inducing anxiety-like behavior. Interestingly, anxiety correlates with circulating free fatty acid levels and can be alleviated by a b-blocker that does not cross the blood brain barrier suggesting a peripheral signal linking metabolism with behavior, however, to date this has not been defined. Herein, we identify that the most upregulated secreted gene product induced by epinephrine within white adipose tissue of mice is growth differentiating factor 15 (GDF15). This increase in GDF15 occurs within one hour and is not observed in liver, brown adipose, kidney, or skeletal muscle, and is also observed with the more specific b2/3-agonist, CL316,243. Genetic inhibition of adipose triglyceride lipase (ATGL), the rate limiting enzyme for the release of free fatty acids in white adipose tissue, or genetic deletion of b-adrenergic receptors, blocks b-adrenergic induced increases in GDF15. Increases in circulating GDF15 are not derived from adipocytes but instead require free fatty acid-induced stimulation of macrophages within white adipose tissue. Remarkably, anxiety-like behavior elicited by epinephrine or restraint stress are eliminated in mice lacking the GDF15 receptor, GFRAL. Importantly in patients with severe burns, increases in catecholamines are associated with GDF15 and this relationship is eliminated with the b-blocker propranolol. These data provide important insight into the mechanisms linking metabolism and behavior and suggest that inhibition of GDF15-GFRAL signaling may be important for reducing acute anxiety.
2024-05-15 | GSE267183 | GEO
Project description:Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.
| S-EPMC7584576 | biostudies-literature
Project description:ObjectiveThe inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity.Methods and resultsWe provide genetic and pharmacological evidence that inhibition of the MEK/ERK pathway in human adipose tissue, mice, and flies all effectively limit adipocyte lipolysis. In complementary findings, we show that genetic and obesity-mediated activation of ERK enhances lipolysis, whereas adipose tissue specific knock-out of ERK2, the exclusive ERK1/2 protein in adipocytes, dramatically impairs lipolysis in explanted mouse adipose tissue. In addition, acute inhibition of MEK/ERK signaling also decreases lipolysis in adipose tissue and improves insulin sensitivity in obese mice. Mice with decreased rates of adipose tissue lipolysis in vivo caused by either MEK or ATGL pharmacological inhibition were unable to liberate sufficient White Adipose Tissue (WAT) energy stores to fuel thermogenesis from brown fat during a cold temperature challenge. To identify a molecular mechanism controlling these actions, we performed unbiased phosphoproteomic analysis of obese adipose tissue at different time points following acute pharmacological MEK/ERK inhibition. MEK/ERK inhibition decreased levels of adrenergic signaling and caused de-phosphorylation of the β3-adrenergic receptor (β3AR) on serine 247. To define the functional implications of this phosphorylation, we showed that CRISPR/Cas9 engineered cells expressing wild type β3AR exhibited β3AR phosphorylation by ERK2 and enhanced lipolysis, but this was not seen when serine 247 of β3AR was mutated to alanine.ConclusionTaken together, these data suggest that ERK activation in adipocytes and subsequent phosphorylation of the β3AR on S247 are critical regulatory steps in the enhanced adipocyte lipolysis of obesity.
| S-EPMC6001906 | biostudies-literature
Project description:ObjectivesObesity is characterized by excessive fat mass and is associated with serious diseases such as type 2 diabetes. Targeting excess fat mass by sustained lipolysis has been a major challenge for anti-obesity therapies due to unwanted side effects. TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity-associated diseases. The molecular mechanism is still largely uncharacterized.MethodsWe used a combination of pharmacological and genetic gain and loss of function approaches. 3T3-L1 and mature murine adipocytes were used for in vitro experiments. Chronic in vivo experiments were conducted on diet-induced obese wild type, ?1, ?2, ?3-adrenergic receptor (AR) deficient and C3aR1 knockout mice. Acute in vivo lipolysis experiments were conducted on Sprague Dawley rats.ResultsWe demonstrated that TLQP-21 does not possess lipolytic properties per se. Rather, it enhances ?-AR activation-induced lipolysis by a mechanism requiring Ca2+ mobilization and ERK activation of Hormone Sensitive Lipase (HSL). TLQP-21 acutely potentiated isoproterenol-induced lipolysis in vivo. Finally, chronic peripheral TLQP-21 treatment decreases body weight and fat mass in diet induced obese mice by a mechanism involving ?-adrenergic and C3a receptor activation without associated adverse metabolic effects.ConclusionsIn conclusion, our data identify an alternative pathway modulating lipolysis that could be targeted to diminish fat mass in obesity without the side effects typically observed when using potent pro-lipolytic molecules.
| S-EPMC5220279 | biostudies-literature
Project description:GDF15 links beta-adrenergic induced lipolysis with anxiety
| PRJNA1110190 | ENA
Project description:Mitogen-activated protein kinase 6 (MAPK6) represents an atypical MAPK also known as extracellular signal-regulated kinase 3 (ERK3), which has been shown to play roles in cell motility and metastasis. ERK3 promotes migration and invasion of lung cancer cells and head and neck cancer cells by regulating the expression and/or activity of proteins involved in cancer progression. For instance, ERK3 upregulates matrix metallopeptidases and thereby promotes cancer cell invasiveness, and it phosphorylates tyrosyl-DNA phosphodiesterase 2, thereby enhancing chemoresistance in lung cancer. Here we discovered that ERK3 plays a converse role in melanoma. We observed that BRAF, an oncogenic Ser/Thr kinase, upregulates ERK3 expression levels by increasing both ERK3 messenger RNA levels and protein stability. Interestingly, although BRAF's kinase activity was required for upregulating ERK3 gene transcription, BRAF stabilized ERK3 protein in a kinase-independent fashion. We further demonstrate that ERK3 inhibits the migration, proliferation and colony formation of melanoma cells. In line with this, high level of ERK3 predicted increased survival among patients with melanomas. Taken together, these results indicate that ERK3 acts as a potent suppressor of melanoma cell growth and invasiveness.
| S-EPMC8378996 | biostudies-literature
Project description:ABHD5 is an essential coactivator of ATGL, the rate-limiting triglyceride (TG) lipase in many cell types. Importantly, ABHD5 also functions as a tumor suppressor, and ABHD5 mRNA expression levels correlate with patient survival for several cancers. Nevertheless, the mechanisms involved in ABHD5-dependent tumor suppression are not known. We found that overexpression of ABHD5 induces cell cycle arrest at the G1 phase and causes growth retardation in a panel of prostate cancer cells. Transcriptomic profiling and biochemical analysis revealed that genetic or pharmacological activation of lipolysis by ABHD5 potently inhibits mTORC1 signaling, leading to a significant downregulation of protein synthesis. Mechanistically, we found that ABHD5 elevates intracellular AMP content, which activates AMPK, leading to inhibition of mTORC1. Interestingly, ABHD5-dependent suppression of mTORC1 was abrogated by pharmacological inhibition of DGAT1 or DGAT2, isoenzymes that re-esterify fatty acids in a process that consumes ATP. Collectively, this study maps out a novel molecular pathway crucial for limiting cancer cell proliferation, in which ABHD5-mediated lipolysis creates an energy-consuming futile cycle between TG hydrolysis and resynthesis, leading to inhibition of mTORC1 and cancer cell growth arrest.
| S-EPMC7949079 | biostudies-literature
Project description:As the fundamental structural protein in mammals, collagen transmits cyclic forces that are necessary for the mechanical function of tissues, such as bone and tendon. Although the tissue-level mechanical behavior of collagenous tissues is well understood, the response of collagen at the nanometer length scales to cyclical loading remains elusive. To address this major gap, we cyclically stretched individual reconstituted collagen fibrils, with average diameter of 145 ± 42 nm, to small and large strains in the partially hydrated conditions of 60% relative humidity. It is shown that cyclical loading results in large steady-state hysteresis that is reached immediately after the first loading cycle, followed thereafter by limited accumulation of inelastic strain and constant initial elastic modulus. Cyclic loading above 20% strain resulted in 70% increase in tensile strength, from 638 ± 98 MPa to 1091 ± 110 MPa, and 70% increase in toughness, while maintaining the ultimate tensile strain of collagen fibrils not subjected to cyclic loading. Throughout cyclic stretching, the fibrils maintained a steady-state hysteresis, yielding loss coefficients that are 5-10 times larger than those of known homogeneous materials in their modulus range, thus establishing damping of nanoscale collagen fibrils as a major component of damping in tissues. STATEMENT OF SIGNIFICANCE: It is shown that steady-state energy dissipation occurs in individual collagen fibrils that are the building blocks of hard and soft tissues. To date, it has been assumed that energy dissipation in tissues takes place mainly at the higher length scales of the tissue hierarchy due to interactions between collagen fibrils and fibers, and in limited extent inside collagen fibrils. It is shown that individual collagen fibrils need only a single loading cycle to assume a highly dissipative, steady-state, cyclic mechanical response. Mechanical cycling at large strains leads to 70% increase in mechanical strength and values exceeding those of engineering steels. The same cyclic loading conditions also lead to 70% increase in toughness and loss properties that are 5-10 times higher than those of engineering materials with comparable stiffness.
| S-EPMC6510236 | biostudies-literature