Leptin mediates postprandial increases in body temperature through hypothalamus–adrenal medulla–adipose tissue crosstalk

Perry, Rachel J.; Lyu, Kun; Rabin-Court, Aviva; Dong, Jianying; Li, Xiruo; Yang, Yunfan; Qing, Hua; Wang, Andrew; Yang, Xiaoyong; Shulman, Gerald I.

doi:10.1172/jci134699

Cited by 28 publications

(22 citation statements)

References 83 publications

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“…WAT is not only a critical energy storage depot, but it also acts as an endocrine organ sensing metabolic signals and secreting hormones and adipocytokines (e.g., leptin and adiponectin) that regulate whole-body energy homeostasis ( 50 – 53 ). Consistent with previous reports ( 14 , 15 , 17 ), we have demonstrated that administration of globular adiponectin results in an improvement in whole-body glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice

Zhang

Goedeke

et al. 2020

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

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101

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Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2–associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membranesn-1,2-DAG–induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation.

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Section: Discussionmentioning

confidence: 99%

Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice

Zhang

Goedeke

et al. 2020

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

Self Cite

101

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“…The interactions of leptin with its longest receptor isoform trigger STAT3 signaling in the hypothalamus, liver, and adipose tissues to coordinate food intake, energy expenditure, and lipid or glucose metabolism. Its actions are compromised by defective mutation, receptor mutation, resistance, and inflammation [ 9 , 14 , 35 , 36 , 41 ]. We previously identified and created a model with leptin mutation, the 145E mice, by replacing Val by Glu in the codon 145.…”

Section: Discussionmentioning

confidence: 99%

“…The consequent adipocytic hyperplasia and hypertrophy increase the release of free fatty acids, proinflammatory cytokines, and adipokines into the blood stream, and lead to chronic and low-grade inflammations. The result is the impairment of insulin actions and glucose utility in the liver, skeletal muscles, and adipose tissues with a series of metabolic abnormalities, and the eventual development of obesity-associated complications [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Several studies have highlighted the crucial role of adipose tissues in metabolic changes, and their targeting for the prevention of obesity-induced complications.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-4 Improves Metabolic Abnormalities in Leptin-Deficient and High-Fat Diet Mice

Lin

Yang

Wang

et al. 2020

IJMS

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Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of obesity involving leptin deficiency and leptin resistance. Leptin-deficient 145E and leptin-resistant high-fat diet (HFD) mice showed lower levels of circulating IL-4. 145E and HFD mice showed a number of abnormalities: Obesity, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, liver injury, and adiposity with concurrent inflammation, decreases in Akt, signal transducer and activator of transcription 3 (STAT3), and STAT6 phosphorylation in the hypothalamus, liver, and epididymal fat. Independent of leptin-deficient obesity and dietary obesity, a course of 8-week IL-4 supplementation improved obesity and impairment in Akt, STAT3, and STAT6 signaling. Amelioration of cytokine expression, despite variable extents, was closely linked with the actions of IL-4. Additionally, the browning of white adipocytes by IL-4 was found in epididymal white adipose tissues and 3T3-L1 preadipocytes. Chronic exercise, weight management, and probiotics are recommended to overweight patients and IL-4 signaling is associated with clinical improvement. Thus, IL-4 could be a metabolic regulator and antiobesity candidate for the treatment of obesity and its complications.

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“…In addition, high O‐GlcNAcylation in adipocytes induces hyperphagia by transcriptionally activating genes that mediate de novo lipid desaturation through the accumulation of N‐arachidonoylethanolamine, an appetite‐inducing cannabinoid 28 . Recently, an elegant study showed that glucose flux has a role in diet‐induced thermogenesis in brown adipose tissue, which is mediated through leptin‐induced adrenal catecholamine secretion 29 . In that study, an increase in O‐GlcNAcylation in adipose tissue was demonstrated after a meal, and this was shown to play a role in the postprandial increase in plasma leptin concentration and diet‐induced thermogenesis.…”

Section: Adipose Tissue: a Key Regulator Of Whole‐body Homeostasismentioning

confidence: 99%

Role of O‐linked N‐acetylglucosamine in the homeostasis of metabolic organs, and its potential links with diabetes and its complications

Morino

Maegawa

2020

J of Diabetes Invest

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Recent studies using genetically manipulated mouse models have shown the pivotal role of O‐linked N‐acetylglucosamine modification (O‐GlcNAcylation) in the metabolism of multiple organs. The molecular mechanism involves the sensing of glucose flux by the hexosamine biosynthesis pathway, which leads to the adjustment of cellular metabolism to protect against changes in the environment of each organ through O‐GlcNAcylation. More recently, not only glucose, but also fluxes of amino acids and fatty acids have been reported to induce O‐GlcNAcylation, affecting multiple cellular processes. In this review, we discuss how O‐GlcNAcylation maintains homeostasis in organs that are affected by diabetes mellitus: skeletal muscle, adipose tissue, liver and pancreatic β‐cells. Furthermore, we discuss the importance of O‐GlcNAcylation in the pathogenesis of diabetic complications. By elucidating the molecular mechanisms whereby cellular homeostasis is maintained, despite changes in metabolic flux, these studies might provide new targets for the treatment and prevention of diabetes and its complications.

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Leptin mediates postprandial increases in body temperature through hypothalamus–adrenal medulla–adipose tissue crosstalk

Cited by 28 publications

References 83 publications

Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice

Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice

Interleukin-4 Improves Metabolic Abnormalities in Leptin-Deficient and High-Fat Diet Mice

Role of O‐linked N‐acetylglucosamine in the homeostasis of metabolic organs, and its potential links with diabetes and its complications

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