Peptides are gaining prominence in nutrition and therapeutics, offering physiological benefits that extend beyond basic dietary requirements. This article explores the significance of peptides in metabolic, behavioral, and musculoskeletal health, with a focus on their therapeutic potential, molecular mechanisms, and bioactivities.
Introduction to Peptides in Nutrition
In recent decades, peptides have emerged as vital components in nutrition, providing physiological advantages that go beyond basic dietary needs. These short chains of amino acids, typically consisting of 2 to 50 residues joined by covalent bonds, are found in various nutrients, including marine organisms (e.g., fish collagen peptides), dairy products (e.g., milk casein hydrolysates), and plant proteins (e.g., rice bran peptides). The activity of these peptides varies based on their constituents and amino acid sequencing.
Peptides have garnered special attention for their physiological activities and health benefits, with studies indicating their role in immune system modulation and muscle protein synthesis. Some food-derived peptides are beneficial for managing and preventing chronic diseases like diabetes, osteoarthritis, and hypertension. Milk-borne peptides, for instance, have a variety of bioactive properties, including opioid, antioxidative, antimicrobial, and cytomodulatory effects. Peptides derived from fish hydrolysate protein can boost neuropeptide release and stimulate metabolic regulation.
Furthermore, peptides contribute to human health in areas such as aging and sports nutrition. Collagen peptides, for example, strengthen muscles when combined with resistance training in older men. Recent advancements in biotechnology have led to the synthesis of peptides that trigger specific functions, resulting in new peptide-based supplements that offer efficient outcomes. Casein-derived peptides induce antihypertensive attributes, while collagen peptides are widely used to enhance skin and joint health. Glucagon-like peptide (GLP-1) is also synthesized to regulate appetite, which is essential in glucose homeostasis.
Collagen peptides can enhance daily living activities, improve physical and mental health, and reduce pain in middle-aged adults, with prospects for more significant advantages among specific groups, such as those engaging in high-frequency workouts and females. Marine-originated peptides are gaining attention for their role in synthesizing novel therapeutic agents due to their distinct morphology, showing promise in combating diabetes, obesity, and other metabolic diseases by altering significant biochemical routes. Research indicates that taste perception varies between males and females, with GLP-1 having a greater tendency to change taste perception in women than in men, providing insights into physiological changes in response to eating habits.
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Despite the considerable advantages of peptides in nutrition, challenges remain regarding their bioavailability and stability. Understanding their action mechanism, proper dosage, and long-lasting consequences is crucial. This systematic review aims to assemble the most recent findings addressing the backgrounds, physiological implications, therapeutic uses, and molecular mechanisms of peptides in nutrition.
Methods of Data Analysis
A systematic evaluation was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed and Scopus databases were used for the search, employing keywords and phrases related to peptides, nano-peptides, short peptides, biopeptides, bioactive peptides, food-derived peptides, nutrition, diet, and supplements. Connective operators "AND" and "OR" were used to find studies in the database.
Selection Criteria
Articles that involved the role of peptides in human nutrition were included. The most recent articles from 2019 onwards were included to capture the most recent developments in this field. Only clinical and randomized controlled trials (RCTs) were considered. This study involved human subjects of all ages, encouraging comprehensive analysis across all life stages. To uphold coherence and legibility, articles published only in English were included.
Research Screening
Numerous studies were found and put through a detailed screening process to ensure their impact and quality. Two independent reviewers evaluated the title and abstract, and then the full texts were screened against preset inclusion and exclusion criteria. Data from defined studies were retrieved using a standard sheet to ensure quality and suitable insights into the significance of peptides in nutrition. Study selection was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
Risk of Bias Assessment
A risk of bias assessment was conducted using the Cochrane RoB 2.0 tool for all selected studies. All trials were rated as low risk in significant domains like randomization process, deviation from intended interventions, missing outcome data, and measurements of outcomes.
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Results of the Study
A total of 17,325 articles from the PubMed and Scopus databases were found during the initial search. After filtering these articles by their abstracts and titles, 16,575 articles were left out, and 750 articles were identified after we narrowed down our investigation to include only articles published since 2019. These 750 articles went through full-text screening, resulting in the inclusion of 458 articles. Out of these 458 articles, only nine articles were close to meeting the full criteria for the systematic review. Subsequently, one more article was left out as it does not show relevance to our ultimate research aim. In the end, eight articles that satisfied our specifications and were taken into consideration for our review.
Study Layout
The first study comprised double-masked, randomized, and crossover trials involving 20 healthy adults (Aged 26 ± 7). Each experiment inspected energy expenditure, blood pressure, and appetite to examine the effect of various calcium sources and protein co-ingestion on postprandial glucagon-like-peptide (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and peptide tyrosine-tyrosine (PYY) responses.
In the second study, 120 overweight men (Aged 30-60) were allocated randomly to three groups, each receiving a placebo, whey protein, and collagen peptide. A double-blind, monocentric, and placebo-controlled RCT studied the effects of a 15 g collagen peptide associated with 12 weeks of a resistance training program on muscle strength and body composition in untrained middle-aged men.
In the third investigation, 86 participants (aged 40-65) were involved. In the fourth study, which was double-masked, placebo-controlled, and randomized, 25 participants (aged 40-65 years) were treated with 15 g collagen peptide (CP) daily and 12 weeks of hypertrophic resistance exercise to analyze the effects on the skeletal muscle proteome.
Two more studies on musculoskeletal health assessment have been reported. Genc et al. investigated the effect of collagen in 32 individuals (aged 35-65 years) over 8 weeks on Kinesiophobia, pain, and physical function of individuals with meniscopathy. Meanwhile, Jerger et al. examined 50 active males (aged 18-40) to assess adaptation in the patellar tendon by exercising a 14-week collagen diet and physical exercises.
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In another crossover, randomized, and placebo-controlled analysis,14 healthy participants (six males, eight females), aged 24.2 ± 2.6, were examined. The effect of GLP-1 on taste preference was examined. The impact of GLP-1 on taste preferences was measured using food illustrations followed by oral sodium load, and all participants received either a GLP-1 or placebo infusion.
In the final study, Jensen et al. carried out a randomized placebo-controlled investigation involving 195 adults (aged 18-65 years) to evaluate the effect of exercise and liraglutide on weight maintenance. This study evaluates weight regain after stopping one year of liraglutide supplements.
Dosage
In the first analysis, each of the 20 participants received one of three supplements: 3745 mg of milk mineral, which contained 2050 mg of calcium and 58.8 g of protein; 4380 mg of calcium citrate, providing 1000 mg of calcium; and 453 mg of protein-rich milk mineral. In the second study, all participants were assigned to receive 15 g (dissolved in 250 mL water) of whey protein, silicon dioxide-containing placebo, or collagen peptides (CP) daily. In the third study, participants were divided into three groups. First, two groups received 10 and 20 g/day of collagen peptides, while the third group got maltodextrin equivalent to the collagen peptide dose. Each individual in the fourth study got 15 g of collagen peptides or a noncaloric placebo. All dosages were taken one hour before the training session to ensure a consistent daily intake.
In one study, the collagen group received one sachet of Naturengen 4 Joint containing 2000 mg of Type I/III collagen peptides, while the other placebo group was treated with the same sachet containing maltodextrin for 8 weeks. In another study, the intervention group was treated with 5 g/day of specific collagen peptide. In comparison, participants in the placebo group received 5 g/day of maltodextrin (placebo) with resistance training.
In another study, participants received 500 mL of placebo and 1.5 pmol/kg/min GLP-1 every three hours. In the final analysis, the liraglutide group was treated with 0.6 mg/day of liraglutide injection for 52 weeks, while the other group received the same dose of inert placebo, not any other active drug.
Measuring Parameters
In this systematic review, peptide sources, physiological effects, and bioavailability are vital parameters for measuring peptide supplementation. In the first study, an inspection of GLP-1 concentration in plasma post-ingestion is measured as the incremental area under the curve (iAUC). To study physiological effects like hormonal levels of GLP-1, GPY, and PYY using ELISA, appetite is measured via a visual analog scale (VAS). The second analysis anthropometrically investigated physiological parameters such as creatine kinase, urea levels, and body weight. Meanwhile, body composition was measured by Dual Energy X-ray Absorptiometry (DXA). In the third study, the physical activity survey, the veteran Rand 12-item Healthy Survey (VR-12), food record, Knee injury, and Osteoarthritis Outcomes Score are considered for measuring parameters.
In the fourth study, body mass, fat-free mass, and fat mass were measured by the Bioelectrical Impedance Analysis System. A dynamometer was used to calculate leg extension maximal voluntary isometric contraction (MViC), and Liquid Chromatography-Mass Spectrometry (LC-MS) was introduced for measuring muscle proteome analysis. In the fifth study, physical function tests, such as Timed Up and Go (TUG), a 6 min walk, the Berg balance scale (BBS), and a stair-climbing Test, were carried out. The Tampa Scale is used for Kinesiophobia (TSK). The Visual Analog Scale (VAS), WOMAC total, KOOS-PS, and Foot Function Index (FFI) were used to measure pain, quality of life, and physical function.
In another investigation, Magnetic resonance imaging (MRI) was used to measure the patellar tendon and the rectus femoris muscle Cross-sectional Area (CSA). The stiffness testing evaluated the patellar tendon’s stiffness. 1-repetition maximum (1 RM) tests assess maximal muscle strength.
In another study, body composition analysis was performed by a Bioelectrical Impedance Analyzer. A digital calculator, the Homeostasis Model Assessment (HOMA), was applied to estimate insulin resistance and sensitivity. Finally, the ELISA ALPCO kit was used to assess the GLP-1 level. In the final study, Dual-Energy X-ray Absorptiometry (DXA) is used to measure body weight, and a cycle ergometer calculates VO2 max, and accelerometers were used to assess physical activity level.
Discussion on the Role of Peptides
Peptides have garnered significant attention in nutrition because of their numerous advantages in multifunctional health and capacity to address global health issues. These peptides are derived from various dietary sources such as plant proteins, meat, fish, and dairy.
Obesity and related diseases, such as type 2 diabetes, hypertension, and cardiovascular disease, are steadily increasing worldwide. Numerous studies have focused on the differentiation and function of brown and beige fat, providing evidence for their therapeutic potential in treating obesity. Peptides, as a class of chemically active substances linked together by amino acids, have specific physiological activities, including browning of white fat. As signal molecules regulated by the neuroendocrine system, polypeptides, such as neuropeptide Y, brain-gut peptide, and glucagon-like peptide, play a role in obesity and its related complications. Peptide drugs have been widely used in the prevention and treatment of metabolic diseases due to their short half-life, small apparent distribution volume, low toxicity, and low side effects.
Peptides and Adipose Tissue
There are two types of adipose tissue in mammals: white adipose tissue (WAT), which stores energy in the form of lipids, and brown adipose tissue (BAT), which produces heat by consuming energy. WAT is widely distributed throughout the body and is responsible for obesity. BAT can be activated by cold stimulation and produce a non-trembling fever, relying on the mitochondrial brown fat uncoupling protein-1 (UCP-1) protein. Individuals with low body fat have higher BAT activity compared with that in individuals with high body fat, indicating its role in reducing obesity. Brown-like adipocytes, also known as beige adipocytes, have been described within the WAT, particularly in white inguinal adipocytes. Beige adipocytes are similar to brown adipocytes morphologically, containing multilocular lipids and a high number of mitochondria enriched by UCP-1. The process that promotes the transformation of white fat to beige fat is called browning of white fat and could be used as a potential strategy to treat obesity. Polypeptides serve an important regulatory role in brown fat activation and differentiation, and the browning of white fat.
Polypeptides: Structure and Function
A polypeptide is a type of small molecular compound composed of amino acids linked by peptide bonds. Polypeptides can be divided into endogenous or exogenous polypeptides, depending on the source. Endogenous polypeptides are important regulators of biological processes, while exogenous polypeptides are bioactive peptides that exist in the natural world, such as in plants or animals. Peptides can act on specific target organs by either paracrine or autocrine signaling. Exogenous polypeptides can be divided into physiological active peptides and food sensory peptides, according to their function.
Mechanism of Action
Peptides can specifically recognize and bind to receptors on the cell surface, thus exerting the effects of agonists or inhibitors. For example, neuropeptide Y (NPY) is involved in the establishment of insulin resistance in adipose tissue via the long-term overexpression of NPY5 receptor in the paraventricular nucleus, while neuromedin S can bind to neuromedin U receptors (NMUR; NMUR1 and NMUR2). Some polypeptides can bind to proteins directly, which hinders the normal function of the protein. A small number of polypeptides can also affect the conformation and folding of proteins by directly binding with target proteins. Some peptides can promote or inhibit the release of specific hormones. The gastric growth hormone releasing polypeptide (ghrelin) is a polypeptide composed of 28 amino acids.
Peptides in Obesity Research
Peptides have the advantage of being stable, having a low molecular weight and high lipophilicity. In recent years, the area of peptidomics has rapidly developed, and the association between numerous polypeptides have been investigated with the occurrence and prevention of obesity and its related complications. Leptin is a protein hormone that is secreted by adipose tissue and participates in the regulation of sugar, fat, and energy metabolism. Studies have revealed that leptin treatment can cause anorexia, physical activity increase, weight loss and lead to endocrine function and metabolic changes, which have a positive effect on the diet and nondigestive behaviors of patients with leptin deficiency. NPY is a type of polypeptide molecule that widely exists in the central and peripheral nervous system and is composed of 36 amino acids. Injection of NPY into the hypothalamus has been revealed to induce appetite and regulate energy metabolism, and the expression level of NPY has previously been associated with leptin. GLP-1 is secreted by ileal endocrine cells and can promote insulin secretion. In the treatment of obesity, it was previously found that GLP-1 and its receptor agonists could inhibit food intake, reduce weight and alleviate obesity. Ghrelin is a 28-amino-acid polypeptide that is secreted by X/A-like cells of the gastric acid secreting glands and is an endogenous ligand of the GH secreting hormone receptor (GHS-R).
Emerging Peptide Therapies for Weight Loss
GLP-1 (glucagon-like peptide-1) agonists are a popular class of peptides for weight loss. They reduce appetite, improve blood sugar control, and enhance metabolic health. Semaglutide, sold under the brand names Wegovy and Ozempic, is FDA-approved for weight loss and diabetes management. Tirzepatide, known by the brand names Mounjaro and Zepbound, is FDA-approved for type 2 diabetes and used off-label for weight loss. A newer peptide, Retatrutide, is a triple receptor agonist in development. Growth hormone releasing peptides (GHRPs) stimulate the release of growth hormone, supporting metabolism, fat loss, and muscle maintenance. AOD-9604 is a fragment of human growth hormone designed to burn fat without affecting blood sugar levels.
Natural Peptides and AI-Driven Discovery
A naturally occurring molecule identified by Stanford Medicine researchers appears similar to semaglutide in suppressing appetite and reducing body weight. The researchers used artificial intelligence to weed through dozens of proteins in a class called prohormones, focusing on the prohormone convertase 1/3, which separates prohormones at specific amino acid sequences and is known to be involved in human obesity. One of the peptide products is glucagon-like peptide 1, or GLP-1, which regulates appetite and blood sugar levels; semaglutide works by mimicking the effect of GLP-1 in the body. The researchers designed a computer algorithm they named Peptide Predictor to identify typical prohormone convertase cleavage sites in all 20,000 human protein-coding genes. A small peptide made up of just 12 amino acids bumped up the cells’ activity tenfold over controls. Obese mice treated with daily injections of BRP for 14 days lost an average of 3 grams - due almost entirely to fat loss - while control animals gained about 3 grams over the same period.
Comparative Analysis: Peptides vs. Ozempic
As Ozempic becomes a household name in medical weight loss, natural peptide therapies such as BPC-157 and MOTS-c are emerging as promising alternatives. Ozempic (semaglutide) is a GLP-1 receptor agonist that mimics a hormone called glucagon-like peptide-1. Patients taking Ozempic often experience significant weight loss over several months. However, the drug is not without drawbacks. Peptides are short chains of amino acids that act as messengers in the body, influencing everything from hormone regulation to cellular repair. BPC-157 can also support gut health, improve insulin sensitivity, and help regulate appetite signals. MOTS-c is a mitochondrial-derived peptide that helps regulate fat metabolism, energy production, and glucose usage. Ozempic typically produces faster weight loss results, especially in the first 3-6 months. Ozempic is associated with gastrointestinal symptoms, while peptides tend to have minimal side effects.
FDA-Approved Peptides for Weight Loss
Recent evidence shows that GLP-1 receptor agonists can help people lose weight by stimulating the release of the hormone insulin, which helps regulate blood sugar, delaying stomach emptying, increasing fullness, reducing appetite, and alleviating food cravings. The best peptides for weight loss are those approved by the Food and Drug Administration (FDA). Examples include:
- Semaglutide: Wegovy injection is FDA approved as a long-term weight loss aid for adults with obesity, alongside a reduced-calorie diet and increased physical activity, adults with overweight, and at least one weight-related condition, such as hypertension, type 2 diabetes, or dyslipidemia, and children ages 12 years or above with a body mass index (BMI) at or above the 95th percentile for their age and sex.
- Liraglutide: The FDA approved liraglutide in 2014 for the treatment of adult obesity, and studies have also shown the drug to be effective in children ages 12 to 18 years.
- Tirzepatide: In 2023, the FDA approved a tirzepatide injection with the brand name Zepbound for weight loss in adults with obesity or overweight and at least one weight-related condition, alongside a reduced calorie diet and increased physical activity.
Safety and Precautions
Using versions of GLP-1 receptor agonists that are not FDA-approved can be unsafe. They could contain harmful ingredients and too much or too little of the active ingredient. They may not contain any of the active ingredients at all. Counterfeit products are available online that may increase the risk of adverse effects. According to the NIDDK, peptides and other weight loss medications may sometimes cause side effects that outweigh the benefits of weight loss. Peptides for weight loss may delay gastric emptying, which can reduce the effectiveness of oral medications. The FDA cautions that both Wegovy and Zepbound may not be suitable for use during pregnancy, as these medications may harm the fetus.
Oral Peptide D3 for Obesity Management
The obesity epidemic and its metabolic complications continue to be a major global public health threat with limited effective treatments, especially drugs that can be taken orally. A 9-amino-acid peptide named D3 was designed and administered orally to germ-free (GF) mice and wild-type (WT) mice, rats, and macaques. A significant body weight reduction was observed both in WT (12%) and GF (9%) mice treated with D3. D3 ameliorated leptin resistance and upregulated the expression of uroguanylin (UGN), which suppresses appetite via the UGN-GUCY2C endocrine axis. Similar effects were also found in diet-induced obese rat and macaque models. D3 is a novel drug candidate for counteracting diet-induced obesity as a non-toxic and bioactive peptide.