Weight loss isn’t just about “eating less and exercising more“; it’s also about the molecular dynamics behind it. While GLP-1 drugs have been a global hit over the past few years, the development of weight loss drugs extends far beyond this one. New metabolic targets are constantly being discovered, and research and clinical progress are accelerating across mechanisms such as appetite regulation, energy metabolism, and lipolysis. In this issue, we’ll review the hottest targets in the weight loss field and see which ones hold the potential to become the next generation of “magic weight loss tools.”
1. Protein-coupled receptor 75 (GPR75)
GPR75 is a member of the G protein-coupled receptor (GPCR) family, belonging to the rhodopsin family and a unique member of the GPCR family. GPR75 is a 540-amino acid protein first discovered by Tarttelin et al. in 1999. The GPR75 gene is most highly expressed in the brain, but is also expressed in the heart, kidney, and prostate. GPR75 as a new obesity target stems from a study published in Science by Regeneron in 2021. Exome sequencing of 645,000 individuals revealed that individuals with heterozygous truncating GPR75 mutations had an average BMI of 1.8 kg/m2 lower, weighed approximately 5.4 kg less, and had a 54% lower risk of obesity. Mouse studies further confirmed that knocking out GPR75 reduced body weight, blood glucose, and insulin levels. Currently, no GPR75-targeted drug is in clinical trials. Since July 2021, following the publication of the Regeneron study, Regeneron and AstraZeneca have collaborated to develop small molecule antagonists/inhibitors targeting GPR75 to combat obesity and its comorbidities. More information on the mechanism of action and research progress of GPR75 >>
2. Activin type 2 receptor (ActRII)
ActRII (including ACVR2A and ACVR2B) belongs to the TGF-β receptor family and regulates multiple physiological processes. Unlike existing weight loss drugs, which are often associated with muscle loss, targeting ActRII signaling has the potential to promote fat loss while increasing muscle mass, thereby mitigating the risk of frailty in the elderly. Currently, there are approximately two ActRII protein products on the market globally, and six ActRII products in clinical trials: four ActRII proteins and two antibodies. Marketed products include Merck’s Sotatercept and Bristol-Myers Squibb’s Luspatercept. Clinically active monoclonal antibodies include Laekna Pharmaceuticals’ LAE102 and Eli Lilly’s Bimagrumab. Learn more about the mechanism of action and research progress of ActRIIs >>
3. Gastric Inhibitory Peptide Receptor (GIPR)
GIPR is a class B1 GPCR primarily located in pancreatic beta cells. It stimulates insulin secretion upon activation by glucagon-like peptide (GLP). Globally, there are approximately 75 GIPR-related drugs, including 30 synthetic peptides, 10 small molecules, approximately 44 dual-targeting drugs (GIPR × GLP1R), and 17 drugs that target GIPR alone. Most are currently in preclinical stages, while only one of the 28 drugs in clinical trials has been approved. These drugs include peptides, small molecules, fusion proteins, and bispecific antibodies. Learn more about the mechanism of action and research progress of GIPRs.
4. Glucagon-like peptide-1 receptor (GLP1R)
GLP1R is a class B1 GPCR primarily located in pancreatic beta cells, with expression also in tissues such as the brain, gastrointestinal tract, and cardiovascular system. Its activation promotes insulin secretion, inhibits glucagon production, delays gastric emptying, increases satiety, and improves cardiovascular function. Currently, there are approximately 413 GLP1R-related drugs in development worldwide, including approximately 110 in preclinical trials and 154 in clinical trials and on the market. Of these, 96 are single-target drugs, while the remainder are dual-target drugs combining with GLP1Rs and GGCGRs. These drugs include peptides, recombinant proteins, small molecules, and fusion proteins. Learn more about the mechanism of action and research progress of GLP1R >>
5. Glucagon receptor (GCGR)
GCGR is a class B GPCR primarily found in the liver and kidneys. It plays a key role in glucose metabolism and blood glucose homeostasis. Upon activation, it promotes glycogenolysis and elevates blood glucose. As a key metabolic target, it participates in numerous human physiological processes and is a valuable drug target for a variety of conditions, including diabetes, metabolic syndrome, osteoporosis, migraine, depression, and anxiety. It plays a particularly important role in the treatment of type 2 diabetes. Currently, 103 related drugs are known worldwide, most of which remain in preclinical development, and only two hormonal drugs have been approved for marketing. Learn more about the mechanism of action and research progress of GCGR >>
6. Melanocortin 4 Receptor (MC4R)
MC4R is a member of the class A GPCR melanocortin receptor family, which also includes MC1R, MC2R, MC3R, and MC5R. MC4R is primarily expressed in the central nervous system and is a receptor located on neurons in the brain that control food intake and energy homeostasis. It plays a key role in regulating appetite, eating behavior, and body weight. Activation of MC4R reduces food intake and increases energy expenditure. Signaling pathways involved in MC4R include the leptin-melanocortin pathway, the G protein signaling pathway, the β-arrestin pathway, and the Ca2+ regulatory pathway. These pathways are all associated with obesity and energy metabolism. Globally, 32 related drugs are under development, including two marketed and four in clinical trials, primarily small molecules and peptides. Learn more about the mechanism of action and research progress of MC4R >>
7. Growth Differentiation Factor 15 (GDF-15)
GDF-15 (also known as MIC-1, PTGF-B, PDF, and NAG-1) is a distantly related member of the TGF-β superfamily. Its actions are multipotent and dependent on the cellular context, primarily anti-inflammatory and pro-fibrotic. Under physiological conditions, it is highly expressed in the placenta, and levels are elevated in pathological states such as injury, ischemia, and metabolic stress. It has been suggested as a potential biomarker for a variety of diseases, including cancer, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and renal injury. Currently, there are 15 GDF-15 drug candidates under development worldwide: 10 in preclinical trials, two in Phase I clinical trials, two in Phase II clinical trials, and one in the approval stage. Learn more about the mechanism of action and research progress of GDF-15 >>
8. NPY Receptor Family
NPY receptors belong to the class A GPCR family, including Y1R, Y2R, Y4R, and Y5R. They bind to NPY, PYY (peptide YY), and PP (pancreatic polypeptide), activating diverse downstream signaling pathways. NPY receptors inhibit cAMP through Gl/O, regulate ion channels, and activate MAPK and PI3K/Akt pathways, collectively regulating appetite, neural excitability, cell survival, and metabolic processes. Within the complex human neural and metabolic network, NPY receptors serve as a crucial signaling hub that simultaneously controls appetite, mood, and energy metabolism. Not only is it a core member of the neuropeptide Y system, it is also highly implicated in a variety of metabolic diseases (such as obesity and diabetes) and neuropsychiatric disorders (such as anxiety and depression). Although NPY receptors show clear potential for targeting numerous diseases, due to functional redundancy and cross-reactivity between receptor subtypes, the difficulty in structural elucidation, and the lack of high-quality proteins available for high-throughput screening, no NPY receptor-targeted drugs have yet been successfully marketed, and most remain in the preclinical or Phase I stages. Learn more about the mechanism of action and research progress of the NPY receptor family >>
9. Other Emerging Targets
In addition to the popular targets mentioned above, other targets for weight loss drugs include serotonin receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7), cannabinoid receptor 1 (CB1), and pancreatic amyloid polypeptide receptors (AMYR). Serotonin receptors regulate satiety and appetite. Historically, drugs (such as lorcaserin) have been used to reduce appetite via 5-HT2C, but some have been withdrawn or restricted due to safety concerns. CB1 is involved in appetite and energy balance. CB1 inhibitors (such as rimonabant) have shown efficacy but have been withdrawn from the market in multiple countries due to psychiatric and emotional side effects. AMYR is a hormone co-secreted with insulin. It significantly delays gastric emptying, increases satiety, and sends satiety signals to the brain. Combining these with GLP-1 receptor agonists can more comprehensively mimic the synergistic effects of multiple hormones after eating, suppressing appetite and slowing digestion at multiple physiological levels. Representative drugs include the combination of Cagrilintide (long-acting AMYR agonist) and Semaglutide, which is currently in Phase III clinical trials, and preliminary data show that the effect is very good.
10. DIMA BIOTECH’s in-stock mAbs and nanodisc MPs support weight loss drug development
DIMA BIOTECH is a biotechnology company focused on providing products and services to biopharmaceutical companies. For antibody drugs, unlike traditional CROs, we offer functionally validated, in-stock lead antibodies with confirmed antibody sequences and validation data. We have also applied for patents on all existing sequences and offer global licensing. You can instantly import data packages for molecular testing without waiting. For small molecule drugs, Dima Biotech’s innovative Nanodisc membrane proteins (MPs) maintain the native structure of multi-transmembrane proteins, making them an optimal solution for small molecule drug screening.
- Progress on Lead Molecules Related to Weight Loss Targets
- List of Nanodisc Target Products
