Functional Significance and Predictive Value of MicroRNAs in Pediatric Obesity: Tiny Molecules with Huge Impact?

Obesity is a major health concern. While some children develop comorbidities such as insulin resistance and low-grade systemic inflammation upon weight gain, others stay metabolically healthy. There is an urgent need for clinically relevant markers with prognostic value related to disease development and intervention success. MicroRNAs (miRNAs) are established biomarkers for several disease states. Herein, we give a brief overview of miRNA biogenesis and function and the potential role of circulating miRNA in the context of pediatric obesity

Two Cases With an Early Presented Proopiomelanocortin Deficiency—A Long-Term Follow-Up and Systematic Literature Review

Proopiomelanocortin (POMC) deficiency is an extremely rare inherited autosomal recessive disorder characterized by severe obesity, adrenal insufficiency, skin hypopigmentation, and red hair. It is caused by pathogenic variants in the POMC gene that codes the proopiomelanocortin polypeptide which is cleaved to several peptides; the most notable ones are adrenocorticotropic hormone (ACTH), alpha- and beta-melanocyte-stimulating hormones (α-MSH and β-MSH); the latter two are crucial in melanogenesis and the energy balance by regulating feeding behavior and energy homeostasis through melanocortin receptor 4 (MC4R). The lack of its regulation leads to polyphagia and early onset severe obesity. A novel MC4R agonist, setmelanotide, has shown promising results regarding weight loss in patients with POMC deficiency. A systematic review on previously published clinical and genetic characteristics of patients with POMC deficiency and additional data obtained from two unrelated patients in our care was performed. A 25-year-old male patient, partly previously reported, was remarkable for childhood developed type 1 diabetes (T1D), transient growth hormone deficiency, and delayed puberty. The second case is a girl with an unusual presentation with central hypothyroidism and normal pigmentation of skin and hair. Of all evaluated cases, only 50% of patients had characteristic red hair, fair skin, and eye phenotype. Central hypothyroidism was reported in 36% of patients; furthermore, scarce adolescent data indicate possible growth axis dysbalance and central hypogonadism. T1D was unexpectedly prevalent in POMC deficiency, reported in 14% of patients, which could be an underestimation. POMC deficiency reveals to be a syndrome with several endocrinological abnormalities, some of which may become apparent with time. Apart from timely diagnosis, careful clinical follow-up of patients through childhood and adolescence for possible additional disease manifestations is warranted

Stabilization of Overweight and Obesity in Slovenian Adolescents and Increased Risk in Those Entering Non-Grammar Secondary Schools

Background/Aim: To estimate overweight and obesity prevalence trends in Slovenian adolescents entering secondary schools in the years 2004, 2009 and 2014 and differences in the prevalence between different types of secondary schools. Methods: Data from 17,538 adolescents entering secondary schools (mean age ± standard deviation 15.4 ± 0.5 years) collected during obligatory medical examination in years 2004, 2009 and 2014 was analyzed. Overweight and obesity were defined using International Obesity Task Force criteria. Results: In 2004-2009 overweight and obesity prevalence increased, especially in males and stabilized thereafter (2009-2014) in both genders. It was significantly higher (p Conclusions: Overweight and obesity prevalence in Slovenian adolescents entering secondary schools stabilized recently. Adolescents attending secondary vocational and technical/professional schools are at an increased risk of overweight and obesity

Interleukin-1β downregulates RBP4 secretion in human adipocytes.

AIMS/HYPOTHESIS: The excessive accumulation of adipose tissue in the obese state is linked to an altered secretion profile of adipocytes, chronic low-grade inflammation and metabolic complications. RBP4 has been implicated in these alterations, especially insulin resistance. The aim of the present study was to determine if a local inflammatory micro-environment in adipose tissue regulates RBP4 expression and secretion. METHODS: Human SGBS and primary adipocytes cultured with conditioned media from human THP-1 macrophages were used as an in vitro model for adipose inflammation. Adipocytes were exposed to recombinant TNF-α, IL-1β, IL-6 or IL-8. In addition, coexpression of IL-1β and RBP4 was measured in adipose tissue samples from 18 healthy females. RBP4 expression was studied by quantitative PCR and ELISA. RESULTS: RBP4 mRNA expression and secretion was significantly reduced upon incubation with macrophage-conditioned media in SGBS adipocytes and human primary adipocytes. Out of several factors studied we identified IL-1β as a new factor regulating RBP4. IL-1β significantly downregulated RBP4 mRNA and secretion in a time- and dose-dependent manner. IL-1β mediated its inhibitory effects on RBP4 expression via IL-1 receptor and NF-κB, as incubation with the IL-1 receptor blocking antibody and the NF-κB inhibitors CAPE and SC-514 reversed its effect. Most interestingly, RBP4 mRNA was negatively correlated with IL-1β mRNA in subcutaneous adipose tissue. CONCLUSIONS: Adipose tissue inflammation as found in the obese state might lead to a downregulation in local RBP4 levels. IL-1β was identified as a major factor contributing to the decrease in RBP4. The increase in circulating RBP4 that often precedes the development of systemic insulin resistance is most likely unrelated to inflammatory processes in adipose tissue

Association of Average Telomere Length with Body-Mass Index and Vitamin D Status in Juvenile Population with Type 1 Diabetes / Povezava Povprečnih Dolžin Telomerov Z Indeksom Telesne Teže in Vitaminom D Pri Mladostnikih S Sladkorno Boleznijo Tipa 1

Izhodišče. Sladkorna bolezen tipa 1 (SBT1) je kronična avtoimunska bolezen, pri kateri hiperglikemija ter zvišana raven oksidativnega stresa in končnih produktov glikacije skupaj z genetskimi in okoljskimi dejavniki privedeta do nastanka diabetičnih zapletov. Krajše dolžine telomerov so povezane s hiperglikemičnimi epizodami in nižjimi serumskimi vrednostmi vitamina D

Regulation of RBP4 production by selected cytokines from MacCM.

<p>SGBS adipocytes were treated with TNF-α, IL-1β, IL-6 or IL-8 for 48 hours. (A) mRNA expression of RBP4 was measured by quantitative PCR. RBP4 mRNA expression was normalized to succinate dehydrogenase complex subunit A (SDHA) and related to medium control using 2^−ΔΔCT method. Data are presented as mean+SEM of three independent experiments. *p<0.05 (treatment vs. vehicle). (B) Accumulation of RBP4 in the medium supernatant was measured by ELISA. Measurements were related to untreated medium control. Data are presented as mean+SEM of three independent experiments. *p<0.05 (treatment vs. vehicle).</p

IL-1β decreases RBP4 production.

<p>SGBS adipocytes were treated with increasing doses of IL-1β (0.05, 0.5, 5, 50 ng/ml) or the corresponding vehicle control. (A) RBP4 mRNA expression was measured by quantitative PCR. RBP4 expression was normalized to succinate dehydrogenase complex subunit A (SDHA) and related to medium control using 2^−ΔΔCT method. Data are presented as mean+SEM of three independent experiments. *p<0.05 (treatment vs. vehicle). (B) Accumulation of RBP4 in the medium supernatant was measured by ELISA. Measurements were related to untreated medium control. Data are presented as mean+SEM of three independent experiments. *p<0.05 (treatment vs. vehicle). (C, D) Human primary adipocytes obtained from three different donors were treated with 5 ng/ml of IL-1β or vehicle. (C) mRNA expression and (D) secretion of RBP4 was performed as described above.*p<0.05 (treatment vs. vehicle). (E) SGBS adipocytes were treated with 5 ng/ml of IL-1β for 24, 48, and 72 hours. mRNA expression of RBP4 was measured by quantitative PCR. RBP4 expression was normalized to SDHA and related to medium control at 0 hours using 2^−ΔΔCT method. *p<0.05 (treatment vs. vehicle).</p

Inhibition of IL-1R1 and NF-κB pathway inhibitor blunted the inhibitory effect of IL-1β on RBP4 production.

<p>(A) SGBS adipocytes were treated with IL-1β (0.5 ng/ml) and/or IL-1 receptor type 1 specific neutralizing antibody (IL-1R1 Ab; 100 µg/ml) or the corresponding vehicle control. RBP4 mRNA expression was measured by quantitative PCR. RBP4 expression was normalized to succinate dehydrogenase complex subunit A (SDHA) and related to medium control using 2^−ΔΔCT method. Data are presented as mean+SEM of three independent experiments. *p<0.05 vehicle vs. IL-1β; ^#p<0.05 IL-1β vs. IL-1β+IL-1R1 Ab. (B) SGBS adipocytes were treated with IL-1β (0.5 ng/ml) alone or in combination with NF-κB inhibitors CAPE (1 µg/ml) or SC-514 (100 µM) respectively. mRNA expression analysis of RBP4 was performed as described above. *p<0.05 vehicle vs. IL-1β; ^#p<0.05 IL-1β vs. IL-1β+CAPE or IL-1β +SC-514. (C, D) SGBS cells were treated with CAPE (1 µg/ml) or SC-514 (100 µM) during the process of adipogenic differentiation. (C) The rate of adipogenic differentiation was determined on day 10. (D) mRNA expression of PPARγ, C/EBPα and C/EBPβ was determined by qPCR. *p<0.05 vehicle vs. SC-514.</p

Macrophage-secreted factors decrease RBP4 production.

<p>SGBS adipocytes (A, B, C) were treated with increasing concentrations of MacCM (5, 10, 20, 50%) or the corresponding vehicle control. (A) Representative pictures of cells treated for 48 hours with 10% of MacCM. (B) RBP4 mRNA expression was measured by quantitative PCR. RBP4 expression was normalized to succinate dehydrogenase complex subunit A (SDHA) and related to medium control using 2^−ΔΔCT method. Data are presented as mean+SEM of three independent experiments. *p<0.05 (treatment vs. vehicle). (C) Accumulation of RBP4 in the medium supernatant was measured by ELISA. Measurements were related to untreated medium control. Data are presented as mean+SEM of three independent experiments. *p<0.05 (treatment vs. vehicle). (D, E) Human primary adipocytes obtained from three different donors were treated with 10% of MacCM or vehicle. (D) mRNA expression and (E) secretion of RBP4 was performed as described above. *p<0.05 (treatment vs. vehicle). (F) SGBS adipocytes were treated with 10% MacCM or vehicle for 24, 48, and 72 hours. mRNA expression of RBP4 was measured by quantitative PCR. RBP4 expression was normalized to SDHA and related to medium control at 0 hours using 2^−ΔΔCT method. *p<0.05 (treatment vs. vehicle).</p

Negative correlation between the relative mRNA expression of RBP4 and IL-1β in human adipose tissue explants.

<p>RBP4 mRNA relative expression ratios in samples from subcutaneous adipose tissue of 18 healthy middle-aged females with a wide range of BMIs were determined by quantitative PCR and normalized to succinate dehydrogenase complex subunit A (SDHA) by 2^−ΔΔCT method. Due to a non-normal distribution, IL-1β mRNA relative expression ratios were subjected to logarithmic transformation. Correlation between RBP4 and IL-1β expression was determined by Pearson correlation coefficient (R = −0.535; p<0.05).</p