In-depth analysis of leptin and obesity genes: the genetic code to scientific weight loss.

Throughout human evolution, those ancestors in the early prehistoric era who were better able to withstand famine were able to reproduce and thrive. This ability to withstand famine implies unique genetic mutations, allowing them to more efficiently convert the energy from food into fat during rare, plentiful meals. Modern humans are descendants of these ancestors with "thrifty genes," resulting in a higher capacity to accumulate fat than burn it, making them prone to obesity due to overeating. Single-gene mutation obesity is relatively rare; genetic factors primarily confer an individual's susceptibility to obesity.

This genetic susceptibility involves multiple genes that influence not only the phenotype but also the phenotype's response to growth, aging, and environmental changes, leading to obesity through the interaction of genes and environment. Nevertheless, single-gene mutations still play a major role in the development of obesity because studying this type of obesity can elucidate the pathogenesis of human obesity.

Currently studied genes related to obesity include the leptin gene, leptin receptor gene, neuropeptide-γ gene, pro-opioid melanocortin (POMC) gene, peroxidase proliferator-activated protein (PPAR) gene, β-adrenergic receptor gene, uncoupling protein gene, prohormone-converting enzyme-1 gene, and melanin receptor-4 gene. Abnormalities in these genes and their expressed proteins are closely related to obesity.

Leptin and Leptin Receptor

In 1958, Heovey's research found that in cross-perfusion in conjoined mice, lesioning the ventral median hypothalamus (VMH) of one mouse caused obesity, while the other mouse starved to death. Therefore, it can be inferred that as body fat accumulates, a satiety molecule is produced in the bloodstream. The mouse with the VMH lesion showed no response to this molecule, while the undamaged mouse connected to it experienced starvation due to the satiety signal. The circulating factor discovered by Heovey is leptin. Adipose tissue is the site of leptin production, which acts on the hypothalamus to regulate body weight.

In 1994, mutations in the obesity gene were discovered in the microophthalmocyte gene and Waved-1 gene cluster near chromosome 6 in congenitally obese C57BL/6J and ob/ob mice. Zhang et al. cloned the obesity gene. The human obesity gene is located on chromosome 7q³-3, approximately 20 kb in length, containing 3 exons (10.6 kb) and 2 introns (2.3 kb). The protein it encodes consists of 167 amino acids with a molecular weight of 16 kDa. It has a 21-amino acid signal peptide at the N-terminus and is a secreted protein. The obesity gene is highly conserved; nucleotide sequence analysis shows that the coding sequence of the obesity gene in humans and mice shares 84% ​​homology.

Studies have found that plasma leptin levels in mice rapidly decrease during starvation, and this effect is reduced after leptin injection. Leptin levels increase with the intake of food or insulin, and decrease during fasting and exercise.

In animal models, leptin's primary function is to regulate body weight by influencing food intake and energy expenditure through the hypothalamus. Leptin reduces food intake and increases energy expenditure, and also affects reproduction and blood cell production. When the obesity gene in mice mutates (e.g., ob/ob mice), gene expression weakens, plasma leptin levels decrease, leading to increased food intake and decreased energy expenditure, resulting in obesity and diabetes. Transducing the ob gene into human mice using a vector can cause these ob/ob mice to lose weight and return to normal blood sugar levels.

However, clinical studies show that leptin levels in the circulatory system are generally increased in obese patients, which contrasts sharply with the decreased plasma leptin levels in obese mice. Furthermore, plasma leptin levels in obese patients are directly proportional to their fat percentage and body mass index (BMI). Therefore, some speculate that the development of obesity in humans is related to the development of leptin receptor resistance. Since the discovery of leptin in 1994, numerous scientific studies have demonstrated a close relationship between the leptin system and human obesity. However, there is no single answer to the question of how the leptin system regulates body weight in the human body.

In 1995, Tartaglia cloned the mouse leptin receptor gene (OB-R) from a choroid plexus cDNA library. The mouse OB-R is a transmembrane receptor composed of 894 amino acids, with an extracellular fragment of 816 amino acids, exhibiting many characteristics of the class I cytokine receptor family. Following the extracellular fragment of OB-R is a transmembrane fragment (23 amino acids) and a short intracellular fragment (34 amino acids). The corresponding human OB-R amino acid sequence shows high homology with the mouse OB-R, with 78% identical extracellular fragments and 71% identical intracellular fragments. The intracellular fragments of both are highly conserved in the last five residues.

There are two types of OB-Rs: long (OB-R) and short (OB-Rs), both with identical extracellular fragments. OB-RMRNAs can be expressed in the brain, heart, placenta, liver, kidney, pancreas, spleen, muscle, thymus, prostate, ovary, small intestine, colon, and adrenal glands. OB-Rs are expressed at relatively high levels in many tissues, while OB-R is highly expressed in the hypothalamus, the region regulating feeding and body weight, and is also expressed in peripheral tissues such as the heart, spleen, lymph nodes, adrenal medulla, and renal medulla.

The main physiological function of OB-Rs is to provide communication between adipose tissue and the central nervous system, together with leptin, enabling leptin to exert its physiological effects. They also participate in the autocrine regulation of leptin. Obese patients often have hyperinsulinemia, insulin resistance, and leptin resistance, indicating an inseparable link between leptin receptors and obesity and related diseases. Leptin regulates energy balance, fat storage, and certain endocrine functions by directly binding to OB-Rs in the central nervous system, and participates in hematopoiesis and reproduction. OB-Rs are located in the hypothalamus and are believed to mediate most or all of the leptin signaling transduction. They transmit signals via JAK to insulin receptor substrate-1 (IRS-1) and mitogen-activated protein (MAPK), activating STAT, which is crucial for the OB-R's role in regulating body weight. OB-Rs are abundant on the granulosa and lamina cells of the ovary. Leptin is present in follicular fluid and can induce biochemical reactions on ovarian cells, preventing the production of estradiol induced by luteinizing hormone (LH), suggesting that leptin has a direct effect on the ovary and influences reproductive fertility.