MAPK Erk5 in Leptin Receptor‒Expressing Neurons Controls Body Weight and Systemic Energy Homeostasis in Female Mice

Horie, Tetsuhiro; Park, Gyujin; Inaba, Yuka; Hashiuchi, Emi; Iezaki, Takashi; Tokumura, Kazuya; Fukasawa, Kazuya; Yamada, Takanori; Hiraiwa, Manami; Kitaguchi, Yuka; Kamada, Hikari; Kaneda, Katsuyuki; Tanaka, Tomohiro; Inoue, Hiroshi; Hinoi, Eiichi

doi:10.1210/en.2019-00090

Cited by 9 publications

(9 citation statements)

References 50 publications

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“…No obvious phenotype has been reported from hepatocyte-specific ERK5 knockout mice [216]. However, ERK5 deficiency in LepR-expressing neurons resulted in an obesity phenotype with enhanced WAT mass due to increased adipocyte size, but only in female mice fed a normal chow diet [217]. Moreover, impaired glucose homeostasis along with decreased physical activity, energy intake, and energy expenditure was observed in these animals.…”

Section: Erk5 Kinasementioning

confidence: 85%

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Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Kassouf

Sumara

2020

Biomolecules

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The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.

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Section: Erk5 Kinasementioning

confidence: 85%

“…Biomolecules 2020, 10, x 18 of 34 but only in female mice fed a normal chow diet [217]. Moreover, impaired glucose homeostasis along with decreased physical activity, energy intake, and energy expenditure was observed in these animals.…”

Section: Discussionmentioning

confidence: 99%

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Kassouf

Sumara

2020

Biomolecules

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“…Analysis Primary costal chondrocytes were prepared from new born mice using a sequential enzymatic digestion method as described previously. 15) Cells were solubilized in lysis buffer containing protease inhibitor cocktail, and then samples were subjected to immunoblotting assay. 16) Antibodies were from the following companies: anti-β-tubulin was from Santa Cruz Biotechnology (Santa Cruz, CA, U.S.A.); anti-Tsc1 and anti-p-p70S6K1 were from Cell Signaling Technology (Danvers, MA, U.S.A.).…”

Section: Culture Of Primary Chondrocytes and Immunoblottingmentioning

confidence: 99%

mTORC1 Overactivation Leads to Abnormalities in Skeletal Development

Iwahashi

Tokumura

Park

et al. 2020

Biological & Pharmaceutical Bulletin

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The mechanistic/mammalian target of rapamycin complex-1 (mTORC1) integrates multiple signaling pathways and regulates various cellular processes. Tuberous sclerosis complex 1 (Tsc1) and complex 2 (Tsc2) are critical negative regulators of mTORC1. Mouse genetic studies, including ours, have revealed that inactivation of mTORC1 in undifferentiated mesenchymal cells and chondrocytes leads to severe skeletal abnormalities, indicating a pivotal role for mTORC1 in skeletogenesis. Here, we show that hyperactivation of mTORC1 influences skeletal development through its expression in undifferentiated mesenchymal cells at the embryonic stage. Inactivation of Tsc1 in undifferentiated mesenchymal cells by paired-related homeobox 1 (Prx1)-Cremediated recombination led to skeletal abnormalities in appendicular skeletons. In contrast, Tsc1 deletion in chondrocytes using collagen type II α1 (Col2a1)-Cre or in osteoprogenitors using Osterix (Osx)-Cre did not result in skeletal defects in either appendicular or axial skeletons. These findings indicate that Tsc complexmediated chronic overactivation of mTORC1 influences skeletal development at the embryonic stage through its expression in undifferentiated mesenchymal cells but not in chondrocytes or osteoprogenitors.

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“…Leptin is an adipokine that functions as a sensor of the energetic status of the organism. It acts centrally on hypothalamic neurons to induce lipolysis, energy expenditure, satiety, and inhibit food intake 4,5 . There is also evidence that leptin can regulate peripheral immune function through its central signaling 6–8 .…”

Section: Introductionmentioning

confidence: 99%

“…It acts centrally on hypothalamic neurons to induce lipolysis, energy expenditure, satiety, and inhibit food intake. 4,5 There is also evidence that leptin can regulate peripheral immune function through…”

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confidence: 99%

Peripheral leptin signaling persists in innate immune cells during diet-induced obesity

Souza-Almeida

Palhinha

Liechocki

et al. 2020

Journal of Leukocyte Biology

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Leptin is a pleiotropic adipokine that regulates immunometabolism centrally and peripherally.Obese individuals present increased levels of leptin in the blood and develop hypothalamic resistance to this adipokine. Here we investigated whether leptin effects on the periphery are maintained despite the hypothalamic resistance. We previously reported that leptin injection induces in vivo neutrophil migration and peritoneal macrophage activation in lean mice through TNF-and CXCL1-dependent mechanisms. However, leptin effects on leukocyte biology during obesity remain unclear. In this study, we investigated the in vivo responsiveness of leukocytes to i.p. injected leptin in mice with diet-induced obesity (DIO). After 14-16 wk, high-sucrose, high-fat diet (HFD)-fed mice showed hyperglycemia, hyperleptinemia, and dyslipidemia compared to normalsucrose, normal-fat diet (ND). Exogenous leptin did not reduce food intake in DIO mice in contrast to control mice, indicating that DIO mice were centrally resistant to leptin. Regardless of the diet, we found increased levels of TNF-and CXCL1 in the animals injected with leptin, alongside a pronounced neutrophil migration to the peritoneal cavity and enhanced biogenesis of lipid droplets in peritoneal macrophages. Supporting our in vivo results, data from ex vivo leptin stimulation experiments confirmed hypothalamic resistance in DIO mice, whereas bone marrow cells responded to leptin stimulation through mTOR signaling despite obesity. Altogether, our results show that leukocytes responded equally to leptin in ND-or HFD-fed mice. These results support a role for leptin in the innate immune response also in obesity, contributing to the inflammatory status that leads to the development of metabolic disease. K E Y W O R D Sadipose tissue, high-fat diet, leptin signaling, leukocytes, macrophages, neutrophils INTRODUCTIONObesity has become a major health problem worldwide. It is associated with various comorbidities including cancer, type 2 diabetes, Abbreviations: DIO, diet-induced obesity or diet-induced obese; EP, epididymal; HFD, high-sucrose, high-fat diet; ND, normal-sucrose, normal-fat diet; RP, retroperitoneal; SC, subcutaneous; TAG, triacylglycerol; WAT, white adipose tissue.cardiovascular diseases, among many others. 1 Several factors, that is, genetics, epigenetics, environment, habits, and diets influence the development of obesity. Regardless of the etiology, one common aspect of obesity is the central resistance to leptin signaling. 2,3 Leptin is an adipokine that functions as a sensor of the energetic status of the organism. It acts centrally on hypothalamic neurons to induce lipolysis, energy expenditure, satiety, and inhibit food intake. 4,5 There is also evidence that leptin can regulate peripheral immune function through

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MAPK Erk5 in Leptin Receptor‒Expressing Neurons Controls Body Weight and Systemic Energy Homeostasis in Female Mice

Cited by 9 publications

References 50 publications

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

mTORC1 Overactivation Leads to Abnormalities in Skeletal Development

Peripheral leptin signaling persists in innate immune cells during diet-induced obesity

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