Involvement of protein tyrosine phosphatases and inflammation in hypothalamic insulin resistance associated with ageing: Effect of caloric restriction

Frutos, Miriam García-San; Fernández-Agulló, Teresa; Carrascosa, J.M.; Horrillo, Daniel; Barrús, María Teresa; Oliveros, Eva; Sierra, Johanna C.; Ros, Manuel

doi:10.1016/j.mad.2012.06.001

Cited by 22 publications

(16 citation statements)

References 63 publications

(70 reference statements)

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“…In contrast, we found no difference between these two groups in prolactin-sensitive STAT gene expression (STAT3, STAT5A, STAT5B, all p >0.67). This novel finding is consistent with evidence implicating PTPRF overexpression as a contributor to insulin resistance in other organ systems [34], [36] and in the pathogenesis of Type II diabetes [37]. Based on these initial findings, we hypothesize that women with decreased insulin sensitivity will experience a more sluggish increase in milk output in response to infant demand as a result of PTPRF overexpression in the mammary gland.…”

Section: Resultssupporting

confidence: 87%

RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals Distinct Gene Expression Profiles at Three Stages of Lactation

et al. 2013

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Aware of the important benefits of human milk, most U.S. women initiate breastfeeding but difficulties with milk supply lead some to quit earlier than intended. Yet, the contribution of maternal physiology to lactation difficulties remains poorly understood. Human milk fat globules, by enveloping cell contents during their secretion into milk, are a rich source of mammary cell RNA. Here, we pair this non-invasive mRNA source with RNA-sequencing to probe the milk fat layer transcriptome during three stages of lactation: colostral, transitional, and mature milk production. The resulting transcriptomes paint an exquisite portrait of human lactation. The resulting transcriptional profiles cluster not by postpartum day, but by milk Na:K ratio, indicating that women sampled during similar postpartum time frames could be at markedly different stages of gene expression. Each stage of lactation is characterized by a dynamic range (105-fold) in transcript abundances not previously observed with microarray technology. We discovered that transcripts for isoferritins and cathepsins are strikingly abundant during colostrum production, highlighting the potential importance of these proteins for neonatal health. Two transcripts, encoding β-casein (CSN2) and α-lactalbumin (LALBA), make up 45% of the total pool of mRNA in mature lactation. Genes significantly expressed across all stages of lactation are associated with making, modifying, transporting, and packaging milk proteins. Stage-specific transcripts are associated with immune defense during the colostral stage, up-regulation of the machinery needed for milk protein synthesis during the transitional stage, and the production of lipids during mature lactation. We observed strong modulation of key genes involved in lactose synthesis and insulin signaling. In particular, protein tyrosine phosphatase, receptor type, F (PTPRF) may serve as a biomarker linking insulin resistance with insufficient milk supply. This study provides the methodology and reference data set to enable future targeted research on the physiological contributors of sub-optimal lactation in humans.

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Section: Resultssupporting

confidence: 87%

RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals Distinct Gene Expression Profiles at Three Stages of Lactation

et al. 2013

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“…This impairment is in accordance with the alteration in insulin signaling that we observed, but it contradicts our hypothesis that food restriction would not alter insulin-dependent AKT phosphorylation in the liver; it may be explained by a degree of insulin alteration. Indeed, food restriction reduced insulin plasma levels but most probably increased animal stress, which may have contributed to the onset of hypothalamic inflammation and the activation of liver p38-MAPK (García-San Frutos et al 2012). It is noteworthy that food restriction has the opposite effect on liver TNFa to that which it has on the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Milk-soluble formula increases food intake and reduces Il6 expression in elderly rat hypothalami

Hamouda¹,

Delplanque²,

Benomar³

et al. 2015

Journal of Endocrinology

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Malnutrition in the elderly is accompanied by several metabolic dysfunctions, especially alterations in energy homeostasis regulation and a loss of insulin responsiveness. Nutritional recommendations aim to enrich food with high protein and energy supplements, and protein composition and lipid quality have been widely studied. Despite the numerous studies that have examined attempts to overcome malnutrition in the elderly through such nutritional supplementation, it is still necessary to study the effects of a combination of protein, lipids, and vitamin D (VitD). This can be done in animal models of elderly malnutrition. In the present study, we investigated the effects of several diet formulae on insulin responsiveness, inflammation, and the hypothalamic expression of key genes that are involved in energy homeostasis control. To mimic elderly malnutrition in humans, elderly Wistar rats were food restricted (R, K50%) for 12 weeks and then refed for 4 weeks with one of four different isocaloric diets: a control diet; a diet where milk soluble protein (MSP) replaced casein; a blend of milk fat, rapeseed, and DHA (MRD); or a full formula (FF) diet that combined MSP and a blend of MRD (FF). All of the refeeding diets contained VitD. We concluded that: i) food restriction led to the upregulation of insulin receptor in liver and adipose tissue accompanied by increased Tnfa in the hypothalamus; ii) in all of the refed groups, refeeding led to similar body weight gain during the refeeding period; and iii) refeeding with MSP and MRD diets induced higher food intake on the fourth week of refeeding, and this increase was associated with reduced hypothalamic interleukin 6 expression.

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“…It is noteworthy that several studies have indicated that the production of pro-inflammatory mediators, such as TNF-α regulate PTP1B overexpression in obesity on the models of in vivo and in vitro [44,45]. In addition, PTP1B was suggested to be a key contributor to TNF-α-induced insulin resistance and inflammatory conditions in obesity by the other study showing that deficiency of PTP1B ameliorates pro-inflammatory TNF-α-induced insulin resistance and obesity-associated inflammation during aging [45,46]. Therefore, it was suggested that PTP1B is implicated in the development of inflammation and insulin resistance associated with obesity during aging [44,45,46].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, PTP1B was suggested to be a key contributor to TNF-α-induced insulin resistance and inflammatory conditions in obesity by the other study showing that deficiency of PTP1B ameliorates pro-inflammatory TNF-α-induced insulin resistance and obesity-associated inflammation during aging [45,46]. Therefore, it was suggested that PTP1B is implicated in the development of inflammation and insulin resistance associated with obesity during aging [44,45,46]. Taken together, penstyrylpyrone ( 1 ) is of interest due to the potential of modulating multiple targets, and may be a potential therapeutic candidate for the treatment of both type II diabetes and inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

PTP1B Inhibitory and Anti-Inflammatory Effects of Secondary Metabolites Isolated from the Marine-Derived Fungus Penicillium sp. JF-55

Lee

Jang

et al. 2013

Marine Drugs

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Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures afforded a new PTP1B inhibitory styrylpyrone-type metabolite named penstyrylpyrone (1), and two known metabolites, anhydrofulvic acid (2) and citromycetin (3). Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, and kinetic analyses of PTP1B inhibition suggested that these compounds inhibited PTP1B activity in a competitive manner. In an effort to gain more biological potential of the isolated compounds, the anti-inflammatory effects of compounds 1–3 were also evaluated. Among the tested compounds, only compound 1 inhibited the production of NO and PGE2, due to the inhibition of the expression of iNOS and COX-2. Penstyrylpyrone (1) also reduced TNF-α and IL-1β production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of penstyrylpyrone (1) on the pro-inflammatory mediators and NF-κB DNA binding activity were associated with the HO-1 expression. Therefore, these results suggest that penstyrylpyrone (1) suppresses PTP1B activity, as well as the production of pro-inflammatory mediators via NF-κB pathway, through expression of anti-inflammatory HO-1.

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Involvement of protein tyrosine phosphatases and inflammation in hypothalamic insulin resistance associated with ageing: Effect of caloric restriction

Cited by 22 publications

References 63 publications

RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals Distinct Gene Expression Profiles at Three Stages of Lactation

RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals Distinct Gene Expression Profiles at Three Stages of Lactation

Milk-soluble formula increases food intake and reduces Il6 expression in elderly rat hypothalami

PTP1B Inhibitory and Anti-Inflammatory Effects of Secondary Metabolites Isolated from the Marine-Derived Fungus Penicillium sp. JF-55

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