Hepatic Acetyl CoA Links Adipose Tissue Inflammation to Hepatic Insulin Resistance and Type 2 Diabetes

Perry, Rachel; Camporez, João Paulo; Kursawe, Romy; Titchenell, Paul M.; Zhang, Dongyan; Perry, Curtis J.; Jurczak, Michael J.; Abulizi, Abudukadier; Han, Myoung Sook; Zhang, Xian Man; Ruan, Hai Bin; Yang, Xiaoyong; Caprio, Sonia; Kaech, Susan M.; Sul, Hei Sook; Birnbaum, Morris J.; Davis, Roger J.; Cline, Gary W.; Petersen, Kitt Falk; Shulman, Gerald I.

doi:10.1016/j.cell.2015.01.012

Cited by 570 publications

(576 citation statements)

References 63 publications

Supporting

Mentioning

547

Contrasting

Unclassified

Order By: Relevance

“…Abolished HGP, increased muscle glucose uptake, and a pronounced antilipolytic WAT response to insulin confirmed that all classical insulin target tissues remained insulin sensitive in HFD-fed AKO/cTg mice and disproved the concept that IR prevented efficient lipid storage in this model. In accordance with the concept that hepatic acetyl-CoA concentrations regulate insulin sensitivity in the liver (44), it is conceivable that defective lipolysis and reduced FA flux from WAT to the liver in AKO/cTg mice leads to decreased hepatic FA oxidation, reduced acetyl-CoA concentrations, and low HGP.…”

Section: Discussionmentioning

confidence: 95%

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Schreiber

Hofer

Taschler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) catabolism. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) characterized by a systemic TG accumulation. Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues. However, neither NLSDM patients nor AKO mice are exceedingly obese. This phenotype is unexpected considering the importance of the enzyme for TG catabolism in white adipose tissue (WAT). In this study, we identified the counteracting mechanisms that prevent excessive obesity in the absence of ATGL. We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumvent the cardiomyopathy and premature lethality observed in AKO mice. AKO/cTg mice were protected from high-fat diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiation. AKO/cTg mice were highly insulin sensitive under hyperinsulinemic-euglycemic clamp conditions, eliminating insulin insensitivity as a possible protective mechanism. Instead, reduced food intake and altered signaling by peroxisome proliferator-activated receptor-gamma (PPAR-γ) and sterol regulatory element binding protein-1c in WAT accounted for the phenotype. These adaptations led to reduced lipid synthesis and storage in WAT of HFD-fed AKO/cTg mice. Treatment with the PPAR-γ agonist rosiglitazone reversed the phenotype. These results argue for the existence of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFDinduced obesity and insulin resistance.E ssentially all organisms face the problem of continuous energy demand in an environment of irregular food supply. To overcome this dilemma, metazoan organisms developed special storage depots for substrates that are used for energy production. In vertebrates, by far the most efficient energy reservoir is adipose tissue (1). This highly expandable organ is able to store all major nutritional components (fat, carbohydrates, and proteins) as triglycerides (TGs). Adipose tissue mass and TG content depend on the balance of anabolic and catabolic pathways. Lipid storage in response to nutrient supply involves the generation of adipocytes (adipogenesis), the induction of fatty acid (FA) synthesis from glucose and amino acids (de novo lipogenesis), and the synthesis of TGs (lipid synthesis). These processes are activated by a complex transcriptional network involving CCAAT/ enhancer-binding proteins (C/EBPs), sterol regulatory enhancer binding proteins (SREBPs), and the heterodimer of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and retinoid-X receptor (RXR) (2, 3).The opposing metabolic pathway of TG catabolism (lipolysis) requires activation of enzymes called lipases. Adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) hydrolyze all three ester bonds of TGs in a stepwise manner to yield FAs and glycerol (4). Lipolysis is an exquisitely regulated proce...

show abstract

Section: Discussionmentioning

confidence: 95%

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Schreiber

Hofer

Taschler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…jci. Hepatic acetyl and malonyl CoA concentrations were measured by liquid chromatography-MS/MS (LC-MS/MS) as described (15). Liver and skeletal muscle triglyceride content were measured in diabetic mice enzymatically using the method of Bligh and Dyer (31), and ceramide concentrations were measured by LC-MS/MS as previously described (32).…”

Section: Methodsmentioning

confidence: 99%

“…In order to better understand the roles of hepatic acetyl CoA and malonyl CoA in mediating leptin's acute effects to reverse DKA, we coinfused acetate in leptin-treated DKA rats to raise hepatic acetyl CoA concentrations to those measured in untreated rats in DKA (Figure 3, A-D). Acetate infusion increased plasma glucose concentrations and HGP 2-fold ( Figure 3, E and F) (15). Interestingly, the 3-fold increase in hepatic acetyl CoA concentrations induced by the acetate infusion was also associated with a striking increase in ketosis, demonstrated by a doubling in both plasma βOHB concentrations and whole-body βOHB turnover ( Figure 3, G and H), without any change in hepatic malonyl CoA content (leptin-treated rats 0.54 ± 0.15, leptin plus acetate-treated rats 0.35 ± 0.08, leptin→leptin plus acetate-treated rats 0.37 ± 0.16 nmol/g; arrow denotes rats that were treated with leptin alone for 4 hours, then infused with leptin plus acetate for the final 2 hours).…”

Section: Introductionmentioning

confidence: 99%

“…In order to determine the physiological role of increased lipolysis in driving hyperglycemia and ketoacidosis in DKA, we next treated a group of leptin-and corticosterone-infused DKA rats with atglistatin, a small-molecule ATGL inhibitor (14,15), prior to infusion with leptin and corticosterone. This intervention lowered rates of endogenous glucose production, lipolysis, and ketogenesis as well as hepatic acetyl CoA content similar to those measured in leptin-treated DKA rats, without affecting plasma glucagon, epinephrine, norepinephrine, growth hormone, IGF-1, hepatic malonyl CoA concentrations (Figure 1, A-H, Figure 2, A-H, and Supplemental Figure 1, A-C).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis

Perry¹,

Peng²,

Abulizi³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

IntroductionRecent studies have demonstrated that leptin, administered either systemically or into the cerebroventricular or hypothalamic space, can lower plasma glucose concentrations and prolong life in insulinopenic rodent models of poorly controlled type 1 diabetes (T1D) (1-4). However, the mechanism by which this occurs has been the subject of recent debate and has been attributed to suppression of hyperglucagonemia or glucagon responsiveness (1, 2, 5-8), improvements in insulin sensitivity (7,9), and activation of Creb-regulated transcription coactivator 1 signaling (10). Furthermore, even less is known regarding the mechanism by which leptin reverses ketaoacidosis in diabetic rodents. In this regard, hepatic ketogenesis is thought to be regulated mostly by malonyl CoA, a key regulator of carnitine palmitoyl transferase-I (CPT-I) activity, which in turn regulates fatty acid transport into the mitochondria (11). However, until recently, the small pool size and lability of hepatic malonyl CoA have prevented direct measurements of malonyl CoA concentrations, making it difficult to examine the role of malonyl CoA in ketogenesis as well as to determine whether leptin-induced increases in hepatic malonyl CoA concentrations are responsible for leptin's ability to reverse ketoacidosis in rodent models of diabetic ketoacidosis (DKA). In a recent study, we found that acute leptin replacement therapy reduces plasma glucose concentrations by suppressing plasma corticosterone concentrations, resulting in lower rates of lipolysis, which in turn leads to reductions in hepatic acetyl CoA content and hepatic gluconeogenesis in 3 rat models of poorly controlled diabetes (12). However, the role of leptin-mediated suppression of hypercorticosteronemia as necessary or sufficient to mediate leptin's acute, insulin-independent effect in T1D has recently been called into question (13) by Morton et al. They found that leptin as well as glucocorticoid receptor blockade had no effect on plasma glucose concentrations in a streptozotocin-treated (STZ-treated) rat model of T1D and that adrenalectomized T1D rats did not exhibit lower plasma glucose concentrations than nonadrenalectomized T1D rats. From these results, they concluded that lowering plasma corticosterone concentrations is neither necessary nor sufficient to mediate leptin's effects to lower plasma glucose concentrations in T1D rodents. However, there are major differences in the STZ-treated T1D rat model that Morton et al. used in their studies compared with the STZ-treated T1D rat model of DKA used in our studies, which could account for these different results. Specifically, Morton et al. used rats that are less insulinopenic than ours and performed mostly chronic studies in fed rats, whereas we performed primarily acute experiments in fasted rats with 5-fold lower plasma insulin concentrations.In order to further characterize the mechanism by which leptin replacement therapy acutely reverses both the increased rates of hepatic glucose production and hepatic ketogenesis a...

show abstract

“…To measure tissue acetyl CoA content, ∼50 mg of tissue was homogenized in 1 mL of 10% (vol/vol) trichloroacetic acid. The extraction and LC/ MS/MS were performed with atom percent enrichments calculated as described previously (38). Total alanine enrichment was measured by GC/MS.…”

Section: Methodsmentioning

confidence: 99%

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Ferris

Perry

Moreira

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

105

View full text Add to dashboard Cite

Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory elementbinding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.T he brain is one of the most cholesterol-rich organs in the body, with cholesterol playing an important role in membrane fluidity, vesicle formation, and synaptogenesis (1). Cholesterol levels are tightly controlled by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor regulating cholesterol synthetic genes (2). In contrast to fatty acids, which are in equilibrium with the rest of the body, nearly all brain cholesterol is synthesized in the brain because cholesterol-carrying lipoproteins, with the exception of some very dense HDL, cannot readily cross the blood-brain barrier (3-5).When cholesterol is abundant, SREBP2 precursor remains sequestered in the endoplasmic reticulum by SREBP cleavage activating protein (SCAP). As cholesterol is needed, SCAP shuttles SREBP2 to the Golgi for cleavage into a transcriptionally active form that translocates to the nucleus, binds to sterol regulatory elements in DNA, and activates transcription of enzymes of cholesterol synthesis (2). Insulin can regulate SREBP2 expression and activity, in part via two insulin-induced regulatory proteins, Insig1 and Insig2 (6, 7). Furthermore, in insulindeficient diabetes, there is a decrease in SREBP2 and SCAP in the brain leading to decreased brain cholesterol synthesis (8). We have previously shown that both neurons and glial cells express SREBP2 and the enzymes of cholesterol synthesis, and in both cell types expression of the cholesterol synthesis pathway is stimulated by insulin (7).Among the subtypes of glia, astrocytes serve the most diverse roles, providing both structural support to neurons and playing a major role in maintaining the blood-brain barrier. In addition, astrocytes provide a variety of metabolic functions, including storage of glycogen and uptake of ions and neurotransmitters from the synaptic cleft (9, 10).Astrocytes/glial cells have also been suggested to play an important role in brain cholesterol metabolism. When neuronallike retinal ganglion cells are grown in culture and expose...

show abstract

Hepatic Acetyl CoA Links Adipose Tissue Inflammation to Hepatic Insulin Resistance and Type 2 Diabetes

Cited by 570 publications

References 63 publications

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Contact Info

Product

Resources

About