Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro

Chacón, Matilde R.; Miranda, Merce; Jensen, Charlotte Harken; Fernández-Real, José Manuel; Vilarrasa, Núria; Gutiérrez, Cristina; Näf, S; Gómez, José Manuel; Vendrell, Joan

doi:10.1038/ijo.2008.40

Cited by 42 publications

(38 citation statements)

References 30 publications

(34 reference statements)

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“…The current findings provide a mechanistic explanation for the observed association between increased levels of DLK1 and impaired insulin sensitivity in diabetic mice (21) and rats (20), in obese patients (46), and in patients with type 2 diabetes (36). Although our studies are conducted in murine models, these findings may be relevant to normal human physiology.…”

Section: Discussionmentioning

confidence: 68%

“…Additionally, the antiresorptive therapy did not affect the risk for developing diabetes in three randomized placebo-controlled trials in postmenopausal women (48). On the other hand, the association between serum increased sDLK1 and the insulin resistance phenotype has been reported in rodent (20,21) and human studies (46) as well as in patients with type 2 diabetes (36,49). Thus, follow-up studies are needed to corroborate the relevance of changes in serum sDLK1 to Glu-OCN regulation of glucose metabolism in humans.…”

Section: Discussionmentioning

confidence: 92%

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DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic b-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic b-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1 2/2 ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1 2/2 mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic b-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.A growing body of work indicates that bone is an endocrine organ that regulates glucose metabolism through, in part, the hormone osteocalcin (OCN). OCN signals in b-cells through its bona fide receptor Gprotein-coupled receptor (Gprc6a) to increase b-cell proliferation and insulin secretion and acts on peripheral tissues to increase energy expenditure (1-3). In turn, insulin signaling in osteoblasts (OBs) stimulates the activation of OCN by promoting its decarboxylation (Glu-OCN) through the bone resorption arm of bone remodeling (1,4). The physiological relevance of these findings have been supported through studies demonstrating skeleton as a site of insulin resistance in mice fed a high-fat diet (5). Moreover, patients with a dominant negative mutation in Gprc6a show evidence of glucose intolerance (3). In all likelihood, the Glu-OCN-insulin feed-forward loop must be under a negative regulation to protect from hypoglycemia. Soluble factors responsible for this regulation have not yet been identified despite the demonstrated ability of transcription factors activating transcription factor 4 (ATF4) and forkhead box protein O1 (FoxO1) to regulate glucose metabolism through a negative regulation of OCN bioavailability (6,7). Delta like-1 (DLK1), also known as preadipocyte factor-1 (Pref-1), is a transmembrane protein belonging to the Notch/serrate/delta family (8,9). The full ectodomain of DLK1 is proteolytically cleaved to generate a soluble active protein named fetal antigen-1 (FA1), which is secreted by endocrine cells of pancreas, ovary, Leydig cells of the testis, adrenal glands, and pituitary gland (10). DLK1 has

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 92%

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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“…These data support a connection between reduced Notch signaling and the pathogenesis of PE. binds and stimulates apoptosis of Notch 2 expressing cells, are increased in obese humans (23,197). While these data provide some evidence that obesity may attenuate Notch signaling, cytotrophoblast migration, and uteroplacental vascular morphogenesis, more research needs to evaluate how metabolic factors impact the Notch signaling pathway.…”

Section: Effects Of Obesity On the Placental Function And Perfusionmentioning

confidence: 97%

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

Spradley

Palei

Granger

2015

American Journal of Physiology-Regulatory, Integrative and Comp

112

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) is a pregnancy-specific disorder typically presenting as new-onset hypertension and proteinuria. While numerous epidemiological studies have demonstrated that obesity increases the risk of PE, the mechanisms have yet to be fully elucidated. Growing evidence from animal and human studies implicate placental ischemia in the etiology of this maternal syndrome. It is thought that placental ischemia is brought about by dysfunctional cytotrophoblast migration and invasion into the uterus and subsequent lack of spiral arteriole widening and placental perfusion. Placental ischemia/ hypoxia stimulates the release of soluble placental factors into the maternal circulation where they cause endothelial dysfunction, particularly in the kidney, to elicit the clinical manifestations of PE. The most recognized of these factors are the anti-angiogenic sFlt-1 and pro-inflammatory TNF-␣ and AT1-AA, which promote endothelial dysfunction by reducing levels of the provasodilator nitric oxide and stimulating production of the potent vasoconstrictor endothelin-1 and reactive oxygen species. We hypothesize that obesity-related metabolic factors increase the risk for developing PE by impacting various stages in the pathogenesis of PE, namely, 1) cytotrophoblast migration and placental ischemia; 2) release of soluble placental factors into the maternal circulation; and 3) maternal endothelial and vascular dysfunction. This review will summarize the current experimental evidence supporting the concept that obesity and metabolic factors like lipids, insulin, glucose, and leptin affect placental function and increase the risk for developing hypertension in pregnancy by reducing placental perfusion; enhancing placental release of soluble factors; and by increasing the sensitivity of the maternal vasculature to placental ischemia-induced soluble factors. body mass index; inflammation; placental ischemia; pregnancy; RUPP; sFlt-1 PE IS A PREGNANCY-SPECIFIC DISORDER typically identified by new-onset hypertension in the second half of pregnancy. Although often accompanied by new-onset proteinuria, PE can be associated with many other signs and symptoms including headaches, visual disturbances, epigastric pain, and the development of edema (4,192). Globally, this disease affects over 8 million pregnancies per year and is estimated to account for 40 -60% of maternal deaths in developing countries (125). In the United States, there was a 25% increase in the rate of PE between the years 1987-2004 (189). This significant increase highlights the importance of understanding how risk factors like obesity play a role in the pathogenesis of this maternal syndrome. Obesity is defined as a body mass index (BMI) of greater than or equal to 30 kg/m 2 . Greater than one-half of pregnant women are overweight or obese (48), and more than two-thirds of reproductive-aged women in the United States are overweight or obese (49). Although mounting epidemiological evidence supports obesity as a major risk factor for PE, the mechanisms linking these two morbidities are...

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“…Confluent SGBS preadipocytes were induced to differentiate to mature adipocytes as described (17). Cells were maintained at 37°C in a humidified atmosphere of 5% CO 2 .…”

Section: Sgbs Cell Culturementioning

confidence: 99%

Adipose Tissue and Serum CCDC80 in Obesity and Its Association with Related Metabolic Disease

Osorio-Conles

Guitart

Moreno-Navarrete

et al. 2017

Mol Med

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Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro

Cited by 42 publications

References 30 publications

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

Adipose Tissue and Serum CCDC80 in Obesity and Its Association with Related Metabolic Disease

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