👤 Paula Walle

Tirzepatide, a dual GLP-1/GIP receptor agonist, is recently approved for the treatment of type 2 diabetes and obesity in adults. Melanocortin-4-receptor (MC4R) deficiency is the most common monogenic cause of obesity and presents with hyperphagia and early onset obesity. While tirzepatide seems to be effective in inducing weight loss in adults with MC4R deficiency, its effects on hyperphagia and weight loss in pediatric patients are unexplored. A 17-year-old girl was admitted to our specialized obesity clinic because of hyperphagia and severe early-onset obesity due to MC4R deficiency. She had an extensive history of lifestyle interventions and psychological support and maintained a high level of physical activity. Despite these efforts, she presented with a BMI of 37 kg/m2 (3.68 SDS) and a substantial psychosocial burden. Vital signs and laboratory evaluations revealed no obesity-related complications. Tirzepatide was initiated at a dose of 2.5 mg weekly and slowly titrated to a maximum dose of 12.5 mg weekly. She initially experienced a substantial reduction in hyperphagia and reported less food noise, a reduction in hunger feelings and prolonged postprandial satiety. However, after 12 weeks hunger scores started to increase again, approaching pre-treatment levels at 28 weeks of follow-up. Metformin was added at 28 weeks in an attempt to better manage of hyperphagia, resulting in a reduction in hyperphagia. Despite these increasing hunger feelings from week 12 to 28, substantial weight loss was achieved, and the patient lost -13.9% of her initial body weight at 28 weeks. After addition of metformin, the patient lost an additional -7% of her weight. Total body weight reduction at week 37 was -20.9%. Tirzepatide was well tolerated, with no adverse effects reported at 41 weeks of follow-up. This case report suggests that tirzepatide is effective in reducing body weight in adolescents with MC4R deficiency. However, the question remains what the effect is on hunger and satiety in the long run and at a higher dose. Cohort studies are needed to assess long-term safety and effectiveness of tirzepatide in the pediatric population and in managing hyperphagia. Show less

Melanocortin-2 receptor accessory protein-2 (MRAP2) modulates the activity of hypothalamic melanocortin-4 (MC4R) and growth hormone-secretagogue (GHSR) receptors, which suppress and promote appetite, respectively. We investigate whether obesity-associated variants of MRAP2 alter their ability to modulate MC4R and GHSR signalling as a possible mechanistic link to the development of obesity. Functional effects of five obesity-associated MRAP2 variants were analysed in HEK293 cells by co-expressing wild-type or variant MRAP2 with MC4R or GHSR. Endpoints included cell-surface and total expression, and ligand-induced second-messenger responses, β-arrestin-2 recruitment, and alternative G-protein activation. MRAP2 decreased basal MC4R cell-surface expression while GHSR cell-surface expression was not affected. In MC4R/MRAP2 expressing cells, maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased. Similarly, ghrelin-induced Ca2+-mobilization in GHSR/MRAP2 expressing cells was increased, but β-arrestin-2 recruitment was suppressed. MRAP2 did not bias G-protein activation by either receptor, although previous reports show MRAP2 biases MC4R signalling towards Gαq/11. The variants did not significantly affect the ability of MRAP2 to modulate MC4R and GHSR signalling. Our results indicate that MRAP2 potentiates the ligand responsiveness of MC4R and GHSR, but has differential effects on β-arrestin-2 recruitment. The MRAP2 variants had no significant effects on the signalling endpoints tested. This suggests that, despite their association with obesity, the variants may be functionally benign, or that the absence of effects reflects limitations inherent to our cellular model. In addition, since MRAP2 can modulate multiple receptors and differentially modulate their signalling, we cannot rule out their influence on body weight regulation via other mechanisms. Show less

Wernicke encephalopathy (WE) is a life-threatening neuropsychiatric disorder caused by thiamine deficiency (TD). One cause of TD is restrictive food intake. We present a girl with severe, treatment-resistant obesity from infancy due to hyperphagia caused by melanocortin 4 receptor (MC4R) deficiency. When aged 16 years, she presented at the emergency department with diplopia, headache, confusion, and ataxia. She had lost 25 kg in the previous 2 months because of anxiety-induced avoidant and restrictive food intake, despite persistent hyperphagia. Her anxiety had been triggered by a period of nausea and fear of vomiting. Neurological examination revealed horizontal and vertical nystagmus and bilateral abducens nerve palsy. Brain MRI showed typical lesions for WE, such as T2/fluid-attenuated inversion recovery hyperintensities in the medial thalamus, leading to a prompt diagnosis, which was later confirmed by a low thiamine value. Daily intravenous thiamine treatment resulted in significant neurological improvement within days. Her eating behavior gradually normalized with psychological support. This case is notable for the coexistence of hyperphagia and restrictive eating in a patient with MC4R deficiency, demonstrating that limited and restrictive food intake can occur even in the presence of monogenic obesity. This suggests complex interactions between hunger and fear pathways, warranting further research to better understand the pathophysiology of hyperphagia and identify new therapeutic targets for MC4R deficiency. Clinicians should consider WE, even in patients with (severe) obesity. Important signs are restrictive eating and neurological symptoms. Prompt thiamine therapy should be initiated when suspected. Show less

The objective of this study was to investigate head circumference (HC) in patients with melanocortin 4 receptor (MC4R) deficiency, the most common cause of monogenetic obesity. Patients with (likely) pathogenic MC4R variants were included. HC, height, and weight were measured, and BMI and standard deviation score (SDS) were calculated. HC SDS was compared to the Dutch reference population. Children were matched 1:1 to a control group with common obesity. Children with MC4R deficiency (n = 63, mean age, 10.32 years) had significantly larger HC (mean, +1.73 SDS) compared to the reference population (0 SDS; p < 0.001) and controls (+1.22 SDS; p = 0.009). In adults (n = 13), HC (median, + 0.86 SDS) did not differ from the reference population (0 SDS; p = 0.152). Macrocephaly (HC ≥ 2 SDS) was present in 43%, 25%, and 23% of pediatric patients with MC4R deficiency, controls, and adult patients, respectively. Children with MC4R deficiency were taller than controls (+1.00 SDS vs. +0.42 SDS; p = 0.016), with similar BMI (+3.99 SDS vs. +3.75 SDS; p = 0.157). HC SDS was associated with height SDS (R Macrocephaly is a common feature of patients with MC4R deficiency. We recommend measuring HC in patients suspected for genetic obesity, as it can be a clue for MC4R deficiency. Show less

Non-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene. Since DNA methylation in the FADS1/2/3 gene cluster has been previously linked with genetic variants and desaturase activities, we now aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes. DNA methylation levels in the CpG sites annotated to FADS2 and FADS1 were analyzed from liver samples of 95 obese participants of the Kuopio Obesity Surgery Study (34 men and 61 women, age 49.5 ± 7.7 years, BMI 43.0 ± 5.7 kg/m We found a negative correlation between DNA methylation levels of cg06781209 and cg07999042 and hepatic FADS2 mRNA expression (both p < 0.05), and with estimated delta-6 desaturase activity based on both liver and serum fatty acids (all p < 0.05). Interestingly, the methylation level of cg07999042 (p = 0.001) but not of cg06781209 (p = 0.874) was associated with FADS2 variant rs174616. Genetic variants of FADS2 may contribute to the pathogenesis of non-alcoholic fatty liver disease by modifying DNA methylation. Show less

Non-alcoholic steatohepatitis (NASH) is associated with changes in fatty acid (FA) metabolism. However, specific changes in metabolism and hepatic mRNA expression related to NASH independent of simple steatosis, obesity and diet are unknown. Liver histology, serum and liver FA composition and estimated enzyme activities based on the FA ratios in cholesteryl esters and triglycerides were assessed in 92 obese participants of the Kuopio Obesity Surgery Study (KOBS) divided to those with normal liver, steatosis or NASH (30 men and 62 women, age 46.8±9.5years (mean±SD), BMI 44.2±6.2kg/m(2)). Plasma FA composition was also investigated in the Metabolic Syndrome in Men (METSIM) Study (n=769), in which serum alanine aminotransferase (ALT) was used as a marker of liver disease. Obese individuals with NASH had higher activity of estimated activities of delta-6 desaturase (D6D, p<0.002) and stearoyl-CoA desaturase 1 (SCD1, p<0.002) and lower activity of delta-5 desaturase (D5D, p<0.002) when compared to individuals with normal liver. Estimated activities of D5D, D6D and SCD1 correlated positively between liver and serum indicating that serum estimates reflected liver metabolism. Accordingly, NASH was associated with higher hepatic mRNA expression of corresponding genes FADS1, FADS2 and SCD. Finally, differences in FA metabolism that associated with NASH in obese individuals were also associated with high ALT in the METSIM Study. We demonstrated alterations in FA metabolism and endogenous desaturase activities that associate with NASH, independent of obesity and diet. This suggests that changes in endogenous FA metabolism are related to NASH and that they may contribute to the progression of the disease. Show less

Obesity is associated with disturbed lipid metabolism and low-grade inflammation in tissues. The aim of this study was to investigate the association between FA metabolism and adipose tissue (AT) inflammation in the Kuopio Obesity Surgery study. We investigated the association of surgery-induced weight loss and FA desaturase (FADS)1/2 genotypes with serum and AT FA profile and with AT inflammation, measured as interleukin (IL)-1β and NFκB pathway gene expression, in order to find potential gene-environment interactions. We demonstrated an association between serum levels of saturated and polyunsaturated n-6 FAs, and estimated enzyme activities of FADS1/2 genes with IL-1β expression in AT both at baseline and at follow-up. Variation in the FADS1/2 genes associated with IL-1β and NFκB pathway gene expression in SAT after weight reduction, but not at baseline. In addition, the FA composition in subcutaneous and visceral fat correlated with serum FAs, and the associations between serum PUFAs and estimated D6D enzyme activity with AT inflammation were also replicated with corresponding AT FAs and AT inflammation. We conclude that the polymorphism in FADS1/2 genes associates with FA metabolism and AT inflammation, leading to an interaction between weight loss and FADS1/2 genes in the regulation of AT inflammation. Show less