Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2′3′-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.

Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.

MODY2 is caused by heterozygous inactivating mutations in the glucokinase (GCK) gene that result in persistent, stable and mild fasting hyperglycaemia (5.6–8.0 mmol/L, glycosylated haemoglobin range of 5.6–7.3%). Patients with GCK mutations usually do not require any drug treatment, except during pregnancy. The GCK gene is considered to be responsible for about 20% of all MODY cases, transcription factors for 67% and other genes for 13% of the cases. Based on our findings, GCK and HNF1A mutations together are responsible for about 90% of the cases in Hungary, this ratio being higher than the 70% reported in the literature. More than 70% of these patients have a mutation in the GCK gene, this means that GCK-MODY is the most prevalent form of MODY in Hungary. In the 91 index patients and their 72 family members examined, we have identified a total of 65 different pathogenic (18) and likely pathogenic (47) GCK mutations of which 28 were novel. In two families, de novo GCK mutations were detected. About 30% of the GCK-MODY patients examined were receiving unnecessary OAD or insulin therapy at the time of requesting their genetic testing, therefore the importance of having a molecular genetic diagnosis can lead to a major improvement in their quality of life.

Objectives: The association between obesity and gastroesophageal reflux disease (GERD) is well-established in adults; however, data in pediatric population is scarce. Our study aimed to assess the association between GERD and health-related quality of life (HRQoL) in overweight children. Methods: From April to August of 2020, we included children aged 7–18 years who attended the Endocrinological Outpatient Clinic at the Paediatric Institute, University of Debrecen, Hungary. The participants completed two questionnaires: the Pediatric Gastroesophageal Reflux Disease Symptom Questionnaire (PGSQ) and the HRQoL questionnaire (PedsQL). Based on the criteria of the World Health Organization (WHO), the patients were categorized into two groups: an overweight or obese group and a group with normal weight. Results: A total of 107 children (51 % female, mean age 13.2 years, 46 % overweight or obese) completed the questionnaires. The median PGSQ score was similar in both groups (4.0 (IQR: 1.0–7.8) vs. 3.0 (IQR: 1.0–7.0), p=0.6). However, the total PedsQL score was significantly lower in the children with overweight or obesity compared to those with normal weight (80.1 (71.1–91.0) vs. 88.0 (76.1–94.6), p=0.031). The PedsQL score was lower among overweight patients with GERD symptoms than that of normal-weight patients without GERD symptoms. Conclusions: Our findings highlight the importance of raising awareness about GERD to enhance the HRQoL and prevent long-term complications in obese children.

Catecholamines are crucial signaling molecules that initiate thermogenesis in adipocytes through beta-adrenergic receptors (ADRBs). Adipocyte catecholamine resistance is a common feature of pediatric obesity, often impeding weight loss and the maintenance of a healthy body fat percentage. Our aim was to identify possible mechanisms that may be responsible for the development of catecholamine resistance in adipocytes. We demonstrate that Lim homeobox 8 (LHX8), a transcription factor previously known for its role in gametogenesis, is essential for catecholamine-induced thermogenesis in human adipocytes. LHX8 is expressed in developing human adipocytes throughout intrauterine and perinatal life, as well as in adulthood, and its expression levels positively correlate with the expression of key thermogenesis genes. Pediatric obesity diminished adipocyte expression of LHX8. Functionally, ADRB stimulation failed to induce thermogenesis in both mouse and human adipocytes when LHX8 was absent. Conversely, LHX8 overexpression enhanced thermogenesis in murine adipocytes. Mechanistically, LHX8 stimulated adipocyte interleukin-33 (IL-33) synthesis in response to ADRB activation, which subsequently increased thermogenic gene expression in both human and mouse adipocytes. In conclusion, adipocyte LHX8 is indispensable for catecholamine-responsive thermogenesis and represents a promising novel therapeutic target to overcome catecholamine resistance and promote effective weight management.