Leptin induces inflammation-related genes in RINm5F insulinoma cells

Hekerman, Paul; Zeidler, Julia; Korfmacher, Stefanie; Bamberg-Lemper, Simone; Knobelspies, Holger; Zabeau, Lennart; Tavernier, Jan; Becker, Walter

doi:10.1186/1471-2199-8-41

Cited by 24 publications

(28 citation statements)

References 65 publications

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“…In addition to controlling appetite, it has been reported that leptin increases the expression of pro-inflammatory cytokines in some cell types, including IL-1β and TNF-α (Hosoi et al, 2000;Aleffi et al, 2005;Shen et al, 2005;Hekerman et al, 2007;Wong et al, 2007;Lafrance et al, 2010); it has also been reported that inflammation increases the levels of leptin and its receptors (Fernandez-Riejos et al, 2010;Gan et al, 2012). Because the expression of LepRa was enhanced in astrocytes in HCD-induced obese PS19 mice, we speculated hyperleptinemia induced inflammatory reactions in astrocytes with enhanced LepRa expression.…”

Section: Leptin Induces Il-1β and Tnf-α Expression In Primary Culturementioning

confidence: 87%

“…Leptin mitigates tau phosphorylation in cultured neuronal cells (Greco et al, 2008), and continuous intraperitoneal injection of leptin in amyloidogenic transgenic mice (CRND8) reduced amyloid burden and tau phosphorylation in vivo (Greco et al, 2010). Additionally, the pro-inflammatory effects of leptin have been shown in a variety of different cell types (Hosoi et al, 2000;Aleffi et al, 2005;Shen et al, 2005;Hekerman et al, 2007;Wong et al, 2007;Lafrance et al, 2010). Hyperleptinemia induced by peritoneal dialysis with glucose-containing fluid increased expression of pro-inflammatory cytokines including TNF-α and IL-6 in visceral adipose tissue in mice.…”

Section: Discussionmentioning

confidence: 99%

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Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: Implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression

Koga

Kojima

Ishikawa

et al. 2014

Neurobiology of Disease

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The number of patients with Alzheimer's disease (AD) is increasing worldwide, and available drugs have shown limited efficacy. Hence, preventive interventions and treatments for presymptomatic AD are currently considered very important. Obesity rates have also been increasing dramatically and it is an independent risk factor of AD. Therefore, for the prevention of AD, it is important to elucidate the pathomechanism between obesity and AD. We generated high calorie diet (HCD)-induced obese tauopathy model mice (PS19), which showed hyperleptinemia but limited insulin resistance. HCD enhanced tau pathology and glial activation. Conversely, voluntary exercise with a running wheel normalized the serum leptin concentration without reducing body weight, and restored the pathological changes induced by HCD. Thus, we speculated that persistent hyperleptinemia played an important role in accelerating pathological changes in PS19 mice. Leptin primarily regulates food intake and body weight via leptin receptor b (LepRb). Interestingly, the nuclear staining for p-STAT3, which was activated by LepRb, was decreased in hippocampal neurons in HCD PS19 mice, indicating leptin resistance. Meanwhile, astroglial activation and the astrocytic expression of a short LepR isoform, LepRa, were enhanced in the hippocampus of HCD PS19 mice. Real-time PCR analysis demonstrated that leptin increased mRNA levels for pro-inflammatory cytokines including IL-1β and TNF-α in primary cultured astrocytes from wild type and LepRb-deficient mice. These observations suggest that persistent hyperleptinemia caused by obesity induces astrocytic activation, astrocytic leptin hypersensitivity with enhanced LepRa expression, and enhanced inflammation, consequently accelerating tau pathology in PS19 mice.

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Section: Leptin Induces Il-1β and Tnf-α Expression In Primary Culturementioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: Implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression

Koga

Kojima

Ishikawa

et al. 2014

Neurobiology of Disease

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“…Administration of IL-12 plus IL-18 induced high levels of mRNA expression of Reg1 and Pap in the pancreas of WT mice, whereas only a small, nonsignificant increase was observed in ob/ob mice. The relative role of leptin and obesity in modulating expression of Reg1 and Pap is not completely clear: whereas leptin induces Pap expression in vitro, this regenerating protein is reduced in vivo in ob/ob mice injected with leptin (43,44). Despite the current uncertainty as to the causes of disregulation of Reg1 and Pap in ob/ob mice, it is noteworthy that severe AP in these mice was associated with lack of induction of these two protective factors.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Sennello¹,

Fayad²,

Pini³

et al. 2008

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

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Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short-and long-term leptin replacement therapy. Shortterm leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.cytokines ͉ inflammation ͉ obesity ͉ pancreas A cute pancreatitis (AP) is an inflammatory disorder that ranges from interstitial edema to confluent necrosis and hemorrhage. In severe cases, progress to circulatory shock, acute lung injury, renal failure, and eventual death may occur (1). Despite some controversy, numerous studies have demonstrated that obesity is associated with increased risk of the severe form of AP and with development of life-threatening complications (2-8). However, the mechanism by which increased adiposity worsens AP remains unknown.Leptin, a protein mainly produced by adipocytes, is a critical regulator of appetite (9). Leptin exerts important regulatory effects on inflammation (10). In the context of AP, the role of leptin remains controversial. In patients with AP, a correlation between serum leptin and disease severity has been reported by some investigators but not by others (11,12). Although in animal models administration of leptin decreases AP severity (13-16), more severe disease is present in leptin-deficient ob/ob and leptin receptordeficient db/db mice as well as leptin-receptor mutant fa/fa rats (17, 18). However, the differential effect of obesity versus leptin deficiency has not been fully investigated.IL-12 and IL-18 are two proinflammatory cytokines that drive the Th1 cell response, characterized by high levels of IFN-␥ (19). Both cytokines are mainly produced by monocytes/macrophages....

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“…Many genes related to inflammation, including ge nes encoding acute phase response proteins such as tPA (tissue plasminogen activator), fibrinogen β, lipoca lin 2, PAP1, preprotachykinin, and MnSOD (manga nese superoxide dismutase) are induced by leptin (53). Leptin levels rapidly increase in acute inflammatory conditions, such as cholecystectomy, acute infection, and sepsis, particularly favored by cytokines, such as TNF a, IL 6, and IL 1β (36).…”

Section: Leptin and Acute Inflammationmentioning

confidence: 99%

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

Paz-Filho

Mastronardi

Franco

et al. 2012

Arq Bras Endocrinol Metab

179

148

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SUMMARYLeptin, the adipokine produced mainly by the white adipose tissue, plays important roles not only in the regulation of food intake, but also in controlling immunity and inflammation. It has been widely demonstrated that the absence of leptin leads to immune defects in animal and human models, ultimately increasing mortality. Leptin also regulates inflammation by means of actions on its receptor, that is widely spread across different immune cell populations. The molecular mechanisms by which leptin determines its biological actions have also been recently elucidated, and three intracellular pathways have been implicated in leptin actions: JAK-STAT, PI3K, and ERK 1/2. These pathways are closely regulated by intracellular proteins that decrease leptin biological activity. In this review, we discuss the molecular mechanisms by which leptin regulates immunity and inflammation, and associate those mechanisms with chronic inflammatory disorders. Arq Bras Endocrinol Metab. 2012;56(9):597-607 Keywords Leptin; immunity; inflammation; cytokines SUMÁRIO A leptina, uma adipocina produzida principalmente pelo tecido adiposo branco, tem um papel importante não somente na regulação da ingestão alimentar, mas também no controle da imunidade e da inflamação. Já foi amplamente demonstrado que a ausência de leptina causa deficiências imunológicas em modelos animais e em humanos, levando ao aumento da mortalidade. A leptina também regula a inflamação por meio da ação em seu receptor, amplamente distribuído em diversos tipos de células do sistema imunológico. Os mecanismos moleculares pelos quais a leptina determina suas ações biológicas foram recentemente elucidados, e três cascatas intracelulares são ativadas pela leptina: JAK-STAT, PI3K e ERK 1/2. Essas cascatas são reguladas por proteínas intracelulares, reduzindo as ações da leptina. Nesta revisão, são discutidos os mecanismos moleculares pelos quais a leptina regula a imunidade e a inflamação, associando-os a enfermidades inflamatórias crônicas. Arq Bras Endocrinol Metab. 2012;56(9):597-607 Descritores

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Leptin induces inflammation-related genes in RINm5F insulinoma cells

Cited by 24 publications

References 65 publications

Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: Implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression

Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: Implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

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