Obesity is associated with a variety of acute and chronic diseases, exerting a significant and direct impact on disease progression. Generally, the main complications caused by obesity include diabetes, hypertension, hyperuricemia, chronic cardiovascular and cerebrovascular diseases, respiratory diseases, obese arthritis, and psychological diseases. For example, with the progressive development of cardiovascular and cerebrovascular diseases, conditions such as myocardial infarction, cerebral infarction, and even death may occur [1].

       In children, obesity can also lead to atherosclerosis and asthma. Studies have found that obesity and asthma may have a bidirectional pathogenic mechanism—low lung capacity and pro-inflammatory factors caused by obesity both play important roles in the pathogenesis of asthma [2]. For pregnant women, pre-pregnancy overweight or obesity is a key factor leading to gestational diabetes and hypertension. Additionally, an excessively high pre-pregnancy body mass index (BMI) can increase the incidence of premature rupture of fetal membranes, cesarean section rate, postpartum hemorrhage rate, and neonatal asphyxia rate [3].

       There are numerous factors contributing to obesity. Generally, obesity is regarded as a chronic metabolic disease caused by the interaction of multiple factors, including genetic factors, environmental factors, and personal lifestyle habits. In modern society, common obesity is basically caused by the intake of high-fat and high-sugar foods in daily life, coupled with lack of exercise—resulting in energy consumption far lower than energy intake, and ultimately leading to excessive fat accumulation in the body that cannot be metabolized normally, resulting in abnormal weight gain.

       Researchers have found that excessive sugar intake in the human body significantly increases the risk of developing 18 types of endocrine diseases, 10 types of cardiovascular and cerebrovascular diseases, 7 types of cancers, and 10 other diseases. Evidence shows that each additional 250 ml/day of sugary beverage intake increases the risk of coronary heart disease by 17% and the related mortality rate by 4%; each additional 25 g/day of sugar intake increases the incidence of pancreatic cancer by 22% [4]. Similarly, excessive fat intake can also significantly increase the risk of fatty liver, hyperlipidemia, and cardiovascular diseases.

       Obesity causes a wide range of complications, involving most organs and circulatory systems of the human body. The harm is significant, and most of these complications are chronic, making them easily overlooked.

            Cardiovascular and cerebrovascular diseases：

        Cerebral apoplexy, coronary heart disease, myocardial infarction, etc., caused by long-term chronic diseases such as atherosclerosis and hypertension ;

            Metabolic diseases：

        Metabolic diseases: Hyperlipidemia, hyperuricemia, hyperinsulinemia, diabetes, etc. ;

            Visceral lesions：

        Fatty liver, gallstones, chronic cholecystitis, pancreatitis, renal metabolic disorders and lesions, etc. ;

            Cancers：

        Cancers: Breast cancer, uterine cancer, ovarian cancer, prostate cancer, etc. ;

            Joint diseases and others：

        Lower limb joint wear, gouty arthritis, sleep apnea syndrome, premature rupture of fetal membranes, fetal preterm birth or asphyxia, depression, anxiety, etc. ;

       Driven by factors related to health and appearance, the market for various weight-loss drugs has always remained highly popular. For instance, orlistat capsules exert their weight-loss effect by inhibiting the absorption of triglycerides in the intestines; methotrexate for injection can block cell division by inhibiting cellular DNA synthesis, thereby achieving fat reduction; bevacizumab injection is a recombinant human vascular endothelial growth factor receptor-2 antibody, which can regulate lipoprotein production while inhibiting tumor angiogenesis, thus exhibiting a fat-reducing effect.

       In recent years, drugs targeting the glucagon-like peptide-1 receptor (GLP-1R) have gained great popularity, among which semaglutide developed and produced by Novo Nordisk is the most well-known. This drug is a GLP-1 receptor agonist used for the treatment of type 2 diabetes. While promoting insulin secretion and inhibiting glucagon secretion, it can delay gastric emptying and suppress appetite. Moreover, it is highly praised by patients because it can largely avoid hypoglycemia caused by decreased blood glucose.

       The results of the phase IIIa OASIS 1 study published by the drug in May 2023 showed that semaglutide can effectively achieve an average weight reduction of 17%. In June 2024, it was approved in China for long-term weight management, making it extremely popular. However, when the proportion of weight loss is excessively high, it is generally considered a sign of muscle loss—and muscle loss means an increased risk of diseases such as cardiovascular and cerebrovascular diseases and osteoporosis. Therefore, such weight-loss drugs also need to pay close attention to the unnecessary risks caused by muscle loss.

       Recent studies have shown that activin type II receptor (ActRII) can also achieve good fat reduction effects while avoiding muscle loss caused by excessive weight loss. As a serine/threonine kinase receptor belonging to the transforming growth factor-β (TGF-β) superfamily, ActRII is involved in the regulation of muscle growth and lipid metabolism in vertebrates.

       In adipocytes, activin promotes lipid storage through ActRII. Blocking this signaling pathway can promote fat metabolism, enhance fatty acid oxidation, and generate inductive signals in white adipose tissue to accelerate energy consumption—significantly reducing fat accumulation, effectively improving blood lipid profiles, and preventing the formation of fatty liver. In muscle cells, the signaling pathway mediated by the ActRII receptor can inhibit muscle growth and cause muscle atrophy. Blocking the ActRIIb signal can inhibit muscle atrophy and increase skeletal muscle mass [5-7]; the human body can further consume fat through muscle metabolism.

       In 2023, Eli Lilly’s acquisition of bimagrumab—an ActRII inhibitor originally developed by Novartis—attracted widespread attention. Bimagrumab can block both ActRIIa and ActRIIb to achieve weight loss. The results of a phase II study in patients with type 2 diabetes combined with obesity showed that the total body fat of the participating patients decreased significantly by 20.5%, while the lean body mass increased by 3.6%, with minimal side effects. This undoubtedly opens a new door for weight-loss drugs. Recently, Lakeland Pharma also announced that its self-developed LAE102—an ActRIIa-specific antibody—has entered the clinical stage for obesity treatment, and the company has fully laid out the ActRII pathway and R&D platform.

Results of Bimagrumab Controlled Experiment ^[8]

       In another research direction, researchers can also achieve fat reduction by inhibiting or knocking out activin receptor-like kinase 7 (ALK7).

      ALK7 is a type I receptor of the TGF-β family, and it is currently known to be highly expressed in adipocytes of mice and humans, playing an important role in regulating lipid metabolism and fat mass. Scholars found that the expression level of ALK7 in adipocytes of diabetic patients is significantly higher than that in normal people. In mouse experiments, inhibiting ALK7 in adipocytes of adult mice can significantly reduce diet-induced weight gain and fat accumulation, and reduce adipocyte volume to a certain extent [9].

       In August 2024, Arrowhead Pharmaceuticals announced that it will advance the development of its products ARO-ALK7 and ARO-INHBE—intended for the treatment of obesity and metabolic diseases—to the clinical development stage. Inhibiting these two targets can effectively reduce fat production.

       Returning to the original intention of obesity treatment, regardless of which target is used for drug development, its safety must be ensured.

       Earlier, a nanobody (single-domain antibody, sdAb) fusion protein named everestmab—jointly designed by multiple research institutions including Shanghai Xinpeijing Medical Laboratory and the Department of Laboratory Medicine, Tongji Hospital, Tongji University (Shanghai)—targets GLP-1R. During experiments, it effectively reduced the HOMA-IR index in rats and demonstrated good safety. Additionally, during the experiment, it was found that both the islet area and pancreatic islet number of the rats were improved.

       In the treatment of obesity, we can also utilize the low immunogenicity of nanobodies to design new drug development strategies to modify or improve drug safety.

       NBLST focuses on the development, modification, and application of nanobodies. It has an alpaca breeding base that meets the standards for experimental animals and an independent experimental base. NBLST is committed to building an integrated industry-academia-research public experimental service platform, aiming to provide more professional and cost-effective experimental services for a wide range of biological research institutions, pharmaceutical R&D enterprises, and innovation teams. Researchers from all sectors are welcome to communicate and contact us.