👤 Elif A Oral

Partial lipodystrophy (PL) is a rare disease characterized by selective loss of subcutaneous fat. To evaluate changes in apolipoproteins, hepatokines, hormones, appetite regulators, and inflammatory markers in patients with PL treated with leptin, assess postprandial metabolism and 24-hour dynamics, and identify predictors of hepatic and metabolic response to therapy. We studied 19 subjects from our previous clinical study (NCT01679197), which investigated the effect of leptin on metabolic dysfunction-associated steatohepatitis associated with PL. A mixed-meal test was performed in a subgroup of 14 patients, and paired 24-hour frequent sampling with standardized meals was completed in 5 individuals. Leptin treatment led to reductions in apolipoproteins B, CII, CIII, and E ( Leptin therapy modulates lipid metabolism, postprandial glucose regulation, and appetite signaling in patients with PL, with responses associated with metabolic parameters and carbohydrate intake. Show less

Familial chylomicronemia syndrome (FCS) is a rare, typically debilitating genetic disorder of extreme hypertriglyceridemia associated with high triglyceride levels and elevated risk for recurrent acute pancreatitis. Diagnosis of FCS is frequently delayed due to its rarity, and treatment options are limited. Patients often report history of acute pancreatitis or associated symptoms, including chronic or recurrent abdominal pain, weakness, and fatigue. The hallmark of chylomicronemia (extreme hypertriglyceridemia) syndromes, including FCS, is extremely high triglyceride levels ≥880 mg/dL (10 mmol/L) resistant to conventional triglyceride-lowering medications including statins, fibrates, and omega-3 fatty acids. Validated clinical scoring tools or genetic testing can support diagnosis. Patients must follow a strict FCS-specific diet <15 to 20 g fat/day. Failure to adhere increases the possibility of recurrent acute and chronic pancreatitis and pancreatic dysfunction. Dietary adherence and long-term disease management are extremely challenging for patients. Multidisciplinary clinical teams can improve patient outcomes and quality of life. Therapies that reduce apolipoprotein C-III, a regulator of triglyceride metabolism, offer an FCS treatment option. Olezarsen, a hepatic-targeted Show less

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients. A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system. Show less