Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

Working Hypothesis for Glucose Metabolism and SARS-CoV-2 Replication: Interplay Between the Hexosamine Pathway and Interferon RF5 Triggering Hyperinflammation. Role of BCG Vaccine?

An altered immune response to pathogens has been suggested to explain increased susceptibility to infectious diseases in patients with diabetes. Recent evidence has documented several immunometabolic pathways in patients with diabetes directly related to the COVID-19 infection. This also seems to be the case for prediabetic subjects with proinflammatory insulin resistance syndrome accompanied with prothrombotic hyperinsulinemic and dysglycemic states. Patients with frank hyperglycemia, dysglycemia and/or hyperinsulinemia develop systemic immunometabolic inflammation with higher levels of circulating cytokines. This deleterious scenario has been proposed as the underlying mechanism enhancing a cytokine storm-like hyperinflammatory state in diabetics infected with severe COVID-19 triggering multi-organ failure. Compared with moderately affected COVID-19 patients, diabetes was found to be highly prevalent among severely affected patients suggesting that this non-communicable disease should be considered as a risk factor for adverse outcomes. The COVID-19 pandemic mirrors with the diabetes pandemic in many pathobiological aspects. Our interest is to emphasize the ties between the immunoinflammatory mechanisms that underlie the morbidity and lethality when COVID-19 meets diabetes. This review brings attention to two pathologies of highly complex, multifactorial, developmental and environmentally dependent manifestations of critical importance to human survival. Extreme caution should be taken with diabetics with suspected symptoms of COVID-19 infection.

Cardiovascular disease (CVD) and type 2 diabetes (T2D) are increasing worldwide. This is mainly due to an unhealthy nutrition, implying that variation in CVD risk may be due to variation in the capacity to manage a nutritional load. We examined the genomic basis of postprandial metabolism. Our main purpose was to introduce the GEMM Family Study (Genetics of Metabolic Diseases in Mexico) as a multi-center study carrying out an ongoing recruitment of healthy urban adults. Each participant received a mixed meal challenge and provided a 5-hours’ time course series of blood, buffy coat specimens for DNA isolation, and adipose tissue (ADT)/skeletal muscle (SKM) biopsies at fasting and 3 h after the meal. A comprehensive profiling, including metabolomic signatures in blood and transcriptomic and proteomic profiling in SKM and ADT, was performed to describe tendencies for variation in postprandial response. Our data generation methods showed preliminary trends indicating that by characterizing the dynamic properties of biomarkers with metabolic activity and analyzing multi-OMICS data it could be possible, with this methodology and research design, to identify early trends for molecular biology systems and genes involved in the fasted and fed states.

We discovered two adult sisters in Colombia, lineally consanguineous, with severe obesity and undetectable serum leptin levels despite markedly elevated body fat. Their clinical profile included childhood-onset extreme weight gain, intense hunger, hyperphagia, hypogonadotropic hypogonadism, and family history of obesity. Direct sequencing of the LEP gene revealed a novel homozygous missense mutation in exon 3 (c.350G>T [p.C117F]). The presence of this mutation, undetectable leptin, and severe obesity confirmed a diagnosis of monogenic leptin deficiency. Here we describe the clinical outcomes of a 12-month treatment with recombinant human leptin (metreleptin). Metabolic and endocrine assessments were conducted before and after therapy. Metreleptin therapy significantly reduced BMI: from 59 to 38 kg/m² (OBX1, age 27) and 60 to 48 kg/m² (OBX2, age 24). Total body fat mass decreased, serum lipids normalized, and insulin sensitivity improved. Hypogonadotropic hypogonadism reversed, and menstruation resumed. Thus, metreleptin reversed the major metabolic and endocrine abnormalities associated with leptin deficiency in these sisters. Limitations include the small sample size, absence of a control group, and lack of anti-metreleptin antibody measurements. Nevertheless, our findings support that leptin replacement with metreleptin is currently the only effective hormonal treatment for this monogenic form of human obesity.

Overweight children and childhood obesity are a public health problem in Mexico. Obesity is traditionally assessed using body mass index (BMI), but an excess of adiposity does not necessarily reflect a high BMI. Thus, body composition indexes are a better alternative. Our objective was to generate body composition percentile curves in children from Mexico City. A total of 2026 boys and 1488 girls aged 6 to 12 years old were studied in Mexico City. Body weight, height, and BMI calculation were measured. Total body fat percentage (TBFP) was derived from the skinfold thicknesses, and fat mass (FMI) and free fat mass indexes (FFMI) were calculated. Finally, age- and gender-specifıc smoothed percentile curves were generated with Cole’s Lambda, Mu, and Sigma (LMS) method. In general, height, weight, waist circumference (WC), and TBFP were higher in boys, but FFM was higher in girls. TBFP appeared to increase significantly between ages 8 and 9 in boys (+2.9%) and between ages 10 and 11 in girls (+1.2%). In contrast, FFM% decreased noticeably between ages 8 and 9 until 12 years old in boys and girls. FMI values peaked in boys at age 12 (P97 = 14.1 kg/m²) and in girls at age 11 (P97 = 8.8 kg/m²). FFMI percentiles increase at a steady state reaching a peak at age 12 in boys and girls. Smoothed body composition percentiles showed a different pattern in boys and girls. The use of TBFP, FMI, and FFMI along with BMI provides valuable information in epidemiological, nutritional, and clinical research.