medwireNews: Children with monogenic obesity linked to mutations in the leptin-melanocortin pathway have lower cardiac muscle mass than other obese children, as well as greater tissue storage of sodium (Na+), research suggests.

“The results point towards the role of the melanocortin pathway for cardiac function, tissue Na+ storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients”, say Marcus Kelm, from the German Heart Centre Berlin, and colleagues.

The team explains that adipose tissue secretes leptin that binds to receptors in the hypothalamus, triggering pro-opiomelanocortin (POMC)expressing neurons, which in turn activate melanocortin-4 receptors (MCR4) via melanocyte-stimulating hormone.

Mutations within this pathway have been linked to severe hyperphagia and early-onset obesity, but patients with heterozygous MCR4 mutations appear protected from hypertension, possibly via reduced sympathetic tone, the researchers continue.

Following the discovery of an age-dependent cardiac phenotype in a MC4R knockout mouse model, Kelm and co-workers used cardiac and sodium magnetic resonance imaging techniques to assess 11 monogenic obese patients, of whom five had bi-allelic POMC mutations (median age 15.0 years) and six were heterozygous for MC4R mutations (median age 13.5 years). These individuals were compared with 19 age- and sex-matched obese children without a monogenic aetiology and 12 children with a healthy weight.

As reported in The Journal of Clinical Endocrinology and Metabolism, the ratio of left ventricular (LV) mass to body surface area was significantly lower in patients with a POMC or MC4R mutation than in non-monogenic obese patients, at a median 31.79 and 35.33 versus 41.39 g/m2, respectively.

Patients with a POMC or MC4R mutation also had a significantly lower LV mass than non-monogenic obese controls (77.48 and 75.69 vs 92.97 g/m2) and when grouped together a significantly lower LV end-diastolic volume to body surface area ratio (64.83 vs 78.50 mL/m2).

But only those patients with a MC4R mutation had a significantly lower LV end-systolic volume to body surface area ratio when compared with non-monogenic obese patients (26.50 vs 32.74 mL/m2).

The researchers did not find a difference between monogenic and non-monogenic obese patients, irrespective of mutation type, with regard to ejection fraction, cardiac index, heart rate or body mass index.

Compared with healthy-weight controls, patients with a MC4R mutation and non-monogenic obese individuals had significantly higher systolic blood pressure (136 and 133 vs 104 mmHg, respectively) and diastolic blood pressure (74 and 64 vs 54 mmHg), whereas the systolic and diastolic blood pressure values were not significantly elevated for the POMC mutation patients.

Furthermore, patients with a POMC or MC4R mutation had significantly higher Na+ content in their tissue than healthy-weight controls (14.79 and 16.41 vs 11.47 mmol/L) but a comparable level to that found in the non-monogenic obese individuals (13.33 mmol/L).

Skin water content was significantly higher in the POMC and MC4R mutation patients compared with both the non-monogenic obese and healthy-weight individuals (0.052 and 0.063 AU vs 0.035 and 0.031 AU, respectively), and there was a significant correlation between skin Na+ and water content, the researchers say.

Analysis of the subcutaneous fat compartment again showed significantly higher Na+ in the POMC and MC4R mutation patients than non-monogenic obese individuals (15.65 and 11.17 vs 8.37 mmol/L), but no differences were noted in the muscle or tibia bone.

Kelm and co-authors note that the cardiac phenotype found in the MC4R patients differs slightly from that of the knockout mouse model, possibly due to the young age of the study population or their heterozygous status.

“It will be highly clinically relevant and remains to be further investigated whether the onset of dilatation or deterioration of left ventricular function occur later in life, reflecting the dilative cardiomyopathy phenotype in rodents”, they comment.

While calling for further investigation to “disentangle the underlying mechanism” of the cardiac phenotype associated with mutations in the melanocortin signalling pathway, the team concludes that their research “clearly demonstrates the need to include testing of cardiac function and involvement of cardiologists in the routine clinical work-up of patients with these rare diseases.”

By Lynda Williams

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J Clin Endocrinol Metab 2021; doi: 10.1210/clinem/dgab368

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