Natural Peptides Versus Semaglutide: A Safer Approach to Obesity Management

This paper highlights that while semaglutide is effective for weight loss, it is associated with significant side effects, high cost, and muscle loss. In contrast, natural peptides such as BRP, BPC-157, and MOTS-c demonstrate promising anti-obesity effects with fewer adverse outcomes, improved safety profiles, and potential affordability making them attractive candidates for future therapeutic development. Obesity represents a chronic health condition, characterized by excessive body fat, which is a risk factor for one's health [1]. Obesity fundamentally depends on the body mass index measurement and becomes classified as such when > 30 kg/m2 [1]. Excess body fat creates a heightened risk for cardiovascular disease, type 2 diabetes, and musculoskeletal disorders as well as certain cancers while being one of the main preventable causes of mortality globally. The medical industry has developed numerous pharmaceutical treatments to counter obesity. Ozempic (semaglutide) is one of the leading weight-loss drugs, having been approved by the U.S. Food and Drug Administration (FDA) in December 2017, for obesity treatment based on its demonstrated efficacy. Ozempic assists in weight loss by mimicking the glucagon like peptide-1 hormone, which functions in the gut like influencing gastric emptying, and promoting the growth of beneficial bacteria, etc. Ozempic acts on glucagon like peptide-1 receptors to increase insulin release while decreasing hunger [2]. The medication diminishes glucagon secretion and gastric emptying, thereby reducing nutrient absorption and fat accumulation. Moreover, Ozempic also suppresses the appetite due to its action on the hypothalamus [2]. The effectiveness of Ozempic has been widely demonstrated. Semaglutide treatment effect in people with obesity trials reported a 15%–20% reduction in patient body weight within 68 weeks [3]. While Ozempic is highly effective, it is, however, strongly associated with adverse effects, including pancreatitis, visual disturbances, hypoglycemia, and gastrointestinal symptoms such as nausea, vomiting, and constipation [4]. Moreover, its high cost of approximately 900–1200 USD/month [5] and limited global availability restricts its use by patients. These side effects and contraindications of Ozempic motivated physicians and pharmacists to seek a much more natural alternative to control obesity. Recent studies have shown that natural peptides provide an alternative to pharmacological drugs, including body protection compound157 (BPC-157), brinp-2 related peptide (BRP), and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c). Natural peptides are described as short-chain peptides containing up to fifty amino acid residues [6]. BRP is a 12-amino-acid natural peptide. It activates fos proto-oncogene (FOS) gene expression, a key marker of neuronal activation associated with appetite suppression, in the hypothalamus [7]. Specifically, BRP directly influenced proopiomelanocortin neurons by initiating the intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)- cAMP response element binding protein (CREB)-FOS signaling pathway, thereby suppressing the feeding habits of test animals such as mice, leading to decreased food consumption by up to 50% [8]. In a study on lean, male mice, injecting BRP reduced the food intake by 50% within 1 h [9]. In obese mice, 2 weeks of BRP treatment led to a mean weight loss of 4 g, predominantly from body fat rather than muscle. In contrast, semaglutide resulted in an approximate 9 g of weight loss. This reduction was not only in fats, but also from muscle and bone loss, which raises questions regarding the impact of the long-term use of this drug [9]. BRP also interacts with brain receptors to reduce food intake while promoting fat oxidation without muscle loss [7]. Various amino acid substitution studies have validated that leucine at position 8 is essential for BRP-induced cAMP activation and FOS expression, and that amidation at the C-terminus of BRP is crucial for its biological function, since non-amidated BRP displayed no activity in vitro [8]. Pharmacokinetics indicated that BRP attains a maximum blood concentration within 1-min post-injection, followed by rapid distribution. In mini pigs, administering BRP before feeding decreased food consumption by 50% in just 1 h [8]. Furthermore, many clinical studies indicated that BRP has no toxicological complications even at high doses [10]. Another interesting peptide is the 15-amino-acid BPC-157, which is obtained by enzymatic isolation from a larger protein found in gastric juice. It acts through fat-cell degradation and hunger suppression [11]. BPC-157 has been reported to enhance body composition and reduce inflammation in animal models [11], making it a promising candidate for obesity treatment. In a study, BPC-157 improved body composition and insulin sensitivity in mice by enhancing lean mass and reducing body fat [11]. In addition, BPC-157 treatment was found to elevate mucin production, which plays an important role in preserving intestinal structural integrity [11]. BPC157 is significantly more affordable than semaglutide therapy, instead costing approximately 22–60 USD per 5 mg vial, according to Standard dosage, 250 mcg dose is taken twice a day hence 5 mg vial of BPC-157 lasts for 5 days. The costs of BPC-157 depend on drug quality and the vendor [12]. BPC-157 also demonstrated outstanding stability and bioavailability in the digestive tract; when taken orally, it remains intact [12]. For therapeutic use, it may be delivered subcutaneously depending on the clinical need. Despite these advantages, its broad availability is limited because it has never been patented or subjected to extensive clinical testing. Although rare, minor anxiety was reported in patients with Chronic Fatigue Syndrome [13]. Dog pharmacokinetic studies showed that BPC-157 exhibits linear pharmacokinetics [14]. In rats, favorable responses were observed following a single daily intramuscular injection of 20 or 100 μg, as well as after a single daily intravenous dose of 20 μg [14]. The elimination half-life following a single intravenous injection was 15.2 min, with the compound undetectable in plasma within 4 h' post-administration in mice [14]. Its elimination half-life in mice was reported to be under 30 min [14]. MOTS-c is a peptide sourced from mitochondria and plays a role in weight control and metabolic regulation. It is encoded by a gene present in 12s ribosomal RNA of mitochondria, but its translation occurs in the cytosol, and it translocates to the nucleus under metabolic stress to regulate gene expression by interacting with casein kinase 2, thus effecting molecular signaling [15]. The role of MOTS-c in enhancing insulin sensitivity and maintaining glucose balance was investigated in inbred CD-1 mice consuming a high-fat diet [16]. MOTS-c prevented obesity in mice given the high-fat diet, but had no affect mice on a normal diet [16]. Central administration of MOTS-c in mice increases the level of reproductive hormones such as follicle stimulating hormone, luteinizing hormone, gonadotropin releasing hormone, and testosterone [17]. However, the conditions and underlying mechanisms leading to similar hormonal changes in humans remain unclear. MOTS-c has been introduced by intraperitoneal and intranasal routes in mice, with the intranasal route enhancing brain uptake of the peptide [18]. Its resistance to proteolytic degradation maximizes its functional longevity in the body [18]. In summary, although semaglutide has demonstrated significant weight loss outcomes, its considerable price, constrained accessibility, and negative effects raise issues regarding its longterm usage. Natural peptides, on the other hand, provide a promising action with minimal side effects. To unlock their full potential, future studies should focus on extensive human clinical trials to confirm their safety and effectiveness. Moreover, attention should be focused on creating affordable production techniques and distribution mechanisms to ensure these peptides are available and applicable for regular therapeutic purposes. Muhammad Affan Abid: conceptualization (equal), methodology (equal), supervision (equal), writing – original draft (equal), writing – review and editing (equal). Muhammad Babar Asad: formal analysis (equal), resources (equal), writing – original draft (equal). Muhammad Junaid Razzak: investigation (equal), writing – original draft (equal), writing – review and editing (equal). The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.