β3-Adrenergic Receptor Stimulation Induces E-Selectin-mediated Adipose Tissue Inflammation

Flach, Rachel J. Roth; Matevossian, Anouch; Akie, Thomas E.; Negrin, Kimberly A.; Paul, M.; Czech, Michael P.

doi:10.1074/jbc.m112.412346

Cited by 44 publications

(26 citation statements)

References 49 publications

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“…1 I ). In contrast, rapamycin did not prevent CL-induced inflammation, a well-known side effect (27), in the eWAT (Fig. 1 J ) or depletion of lipid droplets from BAT (Fig.…”

Section: Resultsmentioning

confidence: 87%

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Tran

Mukherjee

et al. 2016

Diabetes

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Rapamycin extends life span in mice, yet paradoxically causes lipid dysregulation and glucose intolerance through mechanisms that remain incompletely understood. Whole-body energy balance can be influenced by beige/brite adipocytes, which are inducible by cold and other stimuli via β-adrenergic signaling in white adipose depots. Induction of beige adipocytes is considered a promising strategy to combat obesity because of their ability to metabolize glucose and lipids, dissipating the resulting energy as heat through uncoupling protein 1. Here, we report that rapamycin blocks the ability of β-adrenergic signaling to induce beige adipocytes and expression of thermogenic genes in white adipose depots. Rapamycin enhanced transcriptional negative feedback on the β3-adrenergic receptor. However, thermogenic gene expression remained impaired even when the receptor was bypassed with a cell-permeable cAMP analog, revealing the existence of a second inhibitory mechanism. Accordingly, rapamycin-treated mice are cold intolerant, failing to maintain body temperature and weight when shifted to 4°C. Adipocyte-specific deletion of the mTORC1 subunit Raptor recapitulated the block in β-adrenergic signaling. Our findings demonstrate a positive role for mTORC1 in the recruitment of beige adipocytes and suggest that inhibition of β-adrenergic signaling by rapamycin may contribute to its physiological effects.

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“…1 I ). In contrast, rapamycin did not prevent CL-induced inflammation, a well-known side effect (27), in the eWAT (Fig. 1 J ) or depletion of lipid droplets from BAT (Fig.…”

Section: Resultsmentioning

confidence: 87%

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Tran

Mukherjee

et al. 2016

Diabetes

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“…Thus, we treated Ldlr −/− mice fed cholesterol-enriched HFD for four weeks, then began injections with β3 adrenergic receptor agonist to assess whether such stimulation would reverse the suppression in circulating monocytes observed at 30°C. Following previously described protocols 35, 36 , treatment with the β3 adrenergic receptor-specific agonist CL-316,243 showed little effects on circulating monocyte numbers in Ldlr −/− mice housed at 30°C on HFD (Online Figure IX A). Following 4 weeks of continuous treatment, plaque area was assessed, but activation of the β3-adrenergic receptor did not influence plaque area in male or female mice in this short period of plaque assessment (Online Figure IX B).…”

Section: Resultsmentioning

confidence: 89%

“…CL-316,243 (Sigma C5976), a β3-specific adrenoceptor agonist, or saline was administered twice-daily (1 mg/kg/day) by intraperitoneal injection for 4 weeks as previously described 35, 36 .…”

Section: Methodsmentioning

confidence: 99%

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

Williams

Elvington

Ivanov

et al. 2017

Circulation Research

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Rationale Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective due to UCP1-dependent thermogenesis. Objective We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression. Methods and Results Using mouse models of atherosclerosis housed at three different ambient temperatures, we observed that cold temperature enhanced while thermoneutral housing temperature inhibited atherosclerotic plaque growth, as did deficiency in UCP1. However, while UCP1 deficiency promoted poor glucose tolerance, thermoneutral housing enhanced glucose tolerance, and this effect held even in the context of UCP1 deficiency. In conditions of thermoneutrality, but not UCP1 deficiency, circulating monocyte counts were reduced, likely accounting for fewer monocytes entering plaques. Reductions in circulating blood monocytes were also found in a large human cohort in correlation with environmental temperature. By contrast, reduced plaque growth in mice lacking UCP1 was linked to lower cholesterol. Through application of a positron emission tomography (PET) tracer to track CCR2+ cell localization and intravital 2-photon imaging of bone marrow, we associated thermoneutrality with an increased monocyte retention in bone marrow. Pharmacological activation of β3 adrenergic receptors applied to mice housed at thermoneutrality induced UCP1 in beige fat pads but failed to promote monocyte egress from the marrow. Conclusions Warm ambient temperature is, like UCP1 deficiency, atheroprotective, but the mechanisms of action differ. Thermoneutrality associates with reduced monocyte egress from the bone marrow in a UCP-1 dependent manner in mice and likewise may also suppress blood monocyte counts in man.

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“…The stromal vascular fraction (SVF) of the visceral adipose tissue (VAT) was isolated and weighed, and subsequent flow cytometry was performed as previously described (14). Briefly, VAT was minced in digestion buffer (5% BSA-2 mg/ml collagenase-HBSS) and incubated in a 37°C water bath for 45 min.…”

Section: Methodsmentioning

confidence: 99%

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

Danai

Flach

Virbasius

et al. 2015

Molecular and Cellular Biology

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bStudies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes. Whole-body glucose homeostasis in humans is maintained by an elaborate physiological system that involves multiorgan regulation. In the postprandial state, glucose and amino acids induce ␤ cells in the pancreas to secrete insulin, promoting glucose uptake in skeletal muscle and adipose tissue while suppressing glucose production from the liver. These effects of insulin to maintain glucose homeostasis can be disrupted in obesity, causing an insulin-resistant state that contributes to elevated blood glucose levels and an increased incidence of type 2 diabetes (T2D) (1). While metformin (thought to mainly affect liver glucose metabolism) and insulin secretagogues are clinical mainstays for the treatment of T2D, further intervention is often required (2). Due to contraindications, treatments that address the underlying peripheral insulin resistance in T2D are now limited to the use of the thiazolidinediones (TZDs), a major drug class that alleviates insulin resistance by targeting peroxisome proliferator-activated receptor gamma (PPAR␥) (3, 4). Thus, novel proteins that could be targeted with drugs to enhance peripheral insulin sensitivity would prove useful in developing therapies for T2D.In screening the adipocyte kinome for such negative regulators of insulin signaling to glucose transport in vitro, we identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a serine/threonine protein kinase with homology to Saccharomyces cerevisiae Ste20 protein kinases (5). Interestingly, single nucleotide polymorphisms (SNPs) in the Ma...

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β3-Adrenergic Receptor Stimulation Induces E-Selectin-mediated Adipose Tissue Inflammation

Cited by 44 publications

References 49 publications

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

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