Peptides For Weight Loss and Fat Burning

Researchers exploring peptides for weight loss may be wondering which compound works best for burning fat.

Weight loss can provide numerous benefits in those struggling with excess body fat and obesity, such as:

• Improved insulin resistance
• Better cardiovascular health
• Lower risk of several chronic and debilitating diseases

To compile our list of the best peptides for weight loss, the experts at Peptides.org have analyzed numerous clinical trials on the topic, examining the peptides’ mechanisms of action, efficacy, and safety profiles of these compounds.

Continue reading to also uncover where scientists can obtain high-quality research peptides for weight loss for their investigative work.

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Top 3 Peptides For Weight Loss and Management

Before we explore the science of peptides for weight loss, here are three noteworthy peptides that should always be considered for weight management research.

They stand out thanks to their demonstrated benefits, promising safety profiles, and positive approval status by the United States Food and Drug Administration (FDA).

1. Tirzepatide

Tirzepatide is a novel dual-incretin receptor agonist that regulates blood sugar and appetite. It is noted for its impressive efficacy in glycemic control and inducing weight loss. Approved for type 2 diabetes (T2D) use and now undergoing phase-3 trials for weight loss, preliminary results highlight a mean 20.9% weight reduction over 72 weeks of tirzepatide administration at the maximum dosage [1, 2, 3, 4, 5].

2. Semaglutide

Semaglutide is likewise an incretin mimetic that is FDA-approved for various applications, including T2D management and weight loss therapy in adults and adolescents. Of note, a 68-week phase-3b trial in non-diabetic overweight adults showed an average weight loss of 15.8%, roughly equivalent to 33.7lb [6, 7, 8, 9].

3. Liraglutide

Liraglutide is yet another incretin analog. It is FDA-approved for indications including T2D, chronic weight management, and weight loss in adults and adolescents. Additionally, researchers are now exploring its potential in managing other conditions like polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD) [9, 10, 11, 12, 13].

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What are Peptides?

Peptides are molecules found in all living organisms, including humans. They are made of amino acids linked via peptide bonds to form a specific sequence that determines their properties.

More specifically, peptides are small proteins, with chains usually made of 2-50 amino acids, and linked in a linear formation, although some have cyclic or branching configurations [14].

This differentiates them from proteins, typically made of one or more polypeptide chains with complex tridimensional configurations, each consisting of hundreds or thousands of amino acids.

Despite their simpler structure, peptides play key roles in a wide variety of biological processes, including but not limited to:

• Acting as cellular messengers
• Hormone regulation
• Antimicrobial defense
• Neurotransmitter regulation

This wide variety of beneficial effects has prompted scientists to develop technologies such as solid-phase peptide synthesis (SPPS), leading to the development of numerous synthetic peptides with potential therapeutic effects.

Many research peptides are also modified versions of their endogenous counterparts for enhanced effectiveness, safety, and specificity. As a result, numerous compounds are currently under active research as promising drug candidates [14].

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What are Weight Loss Peptides?

Several classes of peptides can help facilitate fat burning and weight loss as they mimic the functions of naturally occurring hormones that play roles in energy metabolism, appetite regulation, and fat breakdown. Notable examples include:

• Incretin mimetics mimic the function of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), produced after food consumption to stimulate insulin release and regulate appetite. Incretin mimetics thus also regulate appetite and induce weight loss by suppressing hunger and cravings [3, 15, 16].
• Growth hormone-releasing hormones (GHRHs) stimulate the release of growth hormone (GH), which promotes fat breakdown while notably targeting abdominal and visceral fat [17, 18, 19, 20, 21].
• Growth hormone fragments mimic the ability of GH to stimulate fat breakdown without exerting any of its anabolic effects [22].

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Does Peptide Therapy for Weight Loss Actually Work?

Extensive clinical research, including large phase 3 studies, has shown that peptide-based compounds can help with weight loss in subjects suffering from obesity or abnormal fat accumulation.

For example, incretin mimetics like liraglutide and semaglutide have been FDA-approved for weight loss therapy based on extensive data from clinical development programs [9].

The novel dual-incretin agonist tirzepatide is also under active research and has recently received approval as a weight loss medication [5, 23]. Here is why and how incretin mimetics work for weight loss:

• These peptides work primarily by suppressing appetite and reducing cravings. As a result, subjects significantly reduce their energy intake and lose weight.
• Randomized clinical trials have shown that tirzepatide (15mg/weekly) and semaglutide (1mg/weekly) lead to a significant reduction of food intake and calorie consumption compared to placebo.
• When testing ad libitum (unrestricted, free) food intake, using a buffet-style meal, research has shown that study volunteers given tirzepatide consumed -309.8kcal, while those given semaglutide group consumed -245.5kcal less than the control group [24].

GHRH analogs such as tesamorelin have also been shown to help reduce body weight, particularly in study volunteers with high amounts of abdominal and visceral fat. Here is why these compounds work for weight loss:

• Tesamorelin has been reported to cause a 69% increase in total GH levels (measured as the area under the curve – AUC) in test subjects [25]. GH has well-known lipolytic effects and stimulates the release of fatty acids from adipose tissue, which can be burned for energy.
• After 52 weeks of tesamorelin at 2mg/day, overweight but otherwise healthy study volunteers exhibited a 3.7lb decrease in body fat from baseline measurements. Additionally, there was an 8% reduction in visceral fat since the trial's onset [26].

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Best Peptides For Weight Loss and Management

As mentioned, some of the best peptides for weight loss include incretin mimetics, GHRH analogs, and GH fragments, which work via various mechanisms to reduce body weight.

Below, we will outline the most effective peptides for weight loss while delving deeper into their structure, mechanisms of action, and effects.

Tirzepatide

Tirzepatide, a 39-amino acid peptide, is a novel dual GIP/GLP-1 receptor agonist. Its structure combines elements from the GIP hormone and a GLP-1 receptor agonist called exenatide. Additionally, it possesses a C20 fatty di-acid moiety to improve its half-life [27, 28].

Due to its structural design, tirzepatide exhibits excellent pharmacokinetics, enabling once-weekly administration via subcutaneous injection. While it activates both the GLP-1 and GIP receptors, it is biased towards GIP [29].

Tirzepatide’s mechanisms lead to an enhancement in insulin secretion, suppression of glucagon production, improved glycemic regulation in individuals with T2D, and better appetite control [1, 3].

It is already approved for these indications:

• In 2022, the FDA authorized tirzepatide for T2D treatment under the brand name Mounjaro based on the SURPASS program results, which demonstrated a reduction of up to -3.02% in glycated hemoglobin. It is administered in weekly doses of up to 15mg [1, 30].
• Tirzepatide has also shown positive results in the SURMOUNT program for its efficacy in weight management in non-diabetic adults and its potential to mitigate cardiovascular risks in T2D patients. Findings from phase 3 studies on its weight loss effects indicate notable weight reductions at weekly doses of both 10mg and 15mg, making it an attractive therapeutic for research studies [5, 31, 32].

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Semaglutide

Semaglutide is a synthetic GLP-1 receptor agonist developed by Novo Nordisk in 2012. Its structure comprises 31 amino acids, with 94% similarity to endogenous GLP-1. This enables the activation of GLP-1 receptors in multiple organs and tissues to modulate blood glucose levels and appetite [7, 33].

Further, semaglutide includes an octadecanoic (C-18) diacid component to prolong its half-life to seven days, permitting once-weekly dosing [34, 35].

Following comprehensive clinical development programs, the FDA approved semaglutide in various forms and indications:

• Following the SUSTAIN program, semaglutide received approval for T2D treatment in 2017, under the brand name Ozempic. Subsequent approvals included its use for reducing cardiovascular events in 2020 and a higher 2mg/weekly dosage for T2D in 2022 [36, 37].
• Thanks to another clinical development program called STEP, 2.4mg/weekly semaglutide, marketed as Wegovy, gained approval in 2021 for weight management in adults with a BMI ≥30 or those with a BMI ≥27 accompanied by weight-associated comorbidities. By 2023, this approval was extended to adolescents aged 12 and above with a BMI for age/sex ≥95th percentile [6, 36].

Semaglutide is also the only orally-active GLP-1 receptor agonist approved by the FDA for glycemic management, available under the name Rybelsus since 2019 [38].

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Liraglutide

Liraglutide is a GLP-1 receptor agonist composed of 31 amino acids, exhibiting a 97% similarity to the endogenous GLP-1 hormone [39].

Its binding to GLP-1 receptors promotes insulin synthesis, reduces glucagon release, moderates digestion, and curbs appetite. The peptide's half-life is approximately 13 hours, allowing for once-daily subcutaneous injections [40].

Novo Nordisk pioneered the development of liraglutide in the 1990s, making it one of the more comprehensively researched incretin mimetics as of writing [41]. The FDA has authorized liraglutide for multiple clinical applications:

• Based on the LEAD program, liraglutide received approval for T2D glycemic control in 2010, and it is commercially available as a 1.8mg/daily injection under the brand Victoza. In 2017, the approval was extended to reducing the risk of major adverse cardiovascular events in T2D patients [42, 43].
• By 2014, liraglutide gained approval for chronic weight management in non-diabetic adults based on the results of the SCALE program. It is available in 3mg/daily injections under the brand name Saxenda. This approval was expanded in 2020 to include adolescents aged 12-17 with a BMI for age/sex at ≥95th percentile [44, 45].

Additionally, research is ongoing to assess liraglutide's efficacy in conditions like polycystic ovary syndrome (PCOS), fatty liver disease, and Alzheimer dementia [10, 11, 12, 13].

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Tesamorelin

Tesamorelin (TH9507) is a synthetic analog of GHRH that comprises its same 44 amino acid sequence, but enhanced with a trans-3-hexenoic acid group at the N-terminus. This addition augments the peptide's potency and stability [46].

Consequently, tesamorelin possesses a half-life of approximately 30-40 minutes. Upon binding to receptors of the pituitary gland, it prompts somatotroph cells to release more growth hormone, with a peak in GH levels observed 30-60 minutes post-injection [25, 47].

Increased GH levels stimulate fat tissue catabolism, predominantly targeting adiposity in the abdominal region and visceral fat (fat that accumulates around and inside internal organs) [19, 20, 21].

The Canadian firm Theratechnologies formulated tesamorelin as a treatment for lipodystrophy in HIV/AIDS patients. After favorable phase-3 trials, the FDA approved the peptide for this use in 2010, marketed as Egrifta and Egrifta SV (small volume) [17, 18].

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AOD-9604

Anti-Obesity Drug (AOD) 9604, known as LAT 8881 or tyr-hGH177-191, is a derivative of the C-terminal fragment of GH, synthesized by Metabolic Pharmaceuticals in the early 2000s [22].

This C-terminal fragment, termed hGH 177-191 or AOD-9401, is believed to be responsible for GH's fat-burning effects [48]. AOD-9604 is a modified version incorporating tyrosine at the N-terminus [49].

Aside from this change, its structure mirrors hGH's 177-191 sequence, including the disulfide bridge (Cys182-Cys189) that helps to stabilize the molecule. This structure, paired with the added tyrosine, augments the peptide's stability, enabling oral activity [50, 51].

Thus, AOD-9604 has been researched as an oral weight loss agent in preclinical and clinical settings [52].

For example, in a murine study, obese mice on 250 mg/kg/day of AOD-9604 shed 28% body weight over 14 days, while those on 1 mg/kg/day of HGH lost 40% [53].
Some clinical trials have also reported significant weight loss. Despite this, AOD-9604's development as a weight loss pill was halted in 2007 due to unsatisfactory outcomes in one of the studies [22].

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MOTS-c

Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is a peptide made up of 16 amino acids. It is naturally produced in the human body, more specifically in the mitochondria—the main cellular organelles involved in the energy metabolism of most living cells.

MOTS-c is believed to play a role in managing the expression of nuclear genes within mitochondria, responding to different factors like metabolic stress.

Several animal studies suggest that as a result of MOTS-c interaction on the mitochondria, the peptide can exert beneficial effects on skeletal muscle and fat tissue metabolism:

• One experiment suggests that MOTS-c interacts with the metabolism of skeletal muscle cells, ultimately resulting in increased activation of adenosine monophosphate-activated protein kinase (AMPK). AMPK is an enzyme that acts as a metabolic switch, forcing muscle cells to uptake more glucose and burn it for energy. The researchers reported that MOTS-c applied to mice on a high-fat, high-calorie diet prevented insulin resistance and diet-induced obesity [54].
• Another study reported that MOTS-c may stimulate the “browning” of white (beige) fat cells—a process that normally occurs when core body temperature dips significantly. By stimulating thermogenesis in fat cells, MOTS-c may increase the body’s total energy expenditure and stimulate fat loss [55].

As a result of these effects, MOTS-c is posited to have potential for the management of obesity and related metabolic disorders [56].

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5-Amino-1MQ

5-Amino-1-methylquinolinium (5-Amino-1MQ) is an orally-active, non-peptide molecule that has been researched for its potential effects on weight loss and metabolic health.

The compound was first developed in 2017 as a tool to inhibit the nicotinamide-N-methyltransferase (NNMT) enzyme. Here is what researchers should know about the mechanisms behind 5-Amino-1MQ [57]:

• NNMT plays a role in energy metabolism, particularly within fat cells, via the methylation of nicotinamide (a form of vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor.
• Methylation is an essential step in various processes such as gene expression, including genes that regulate fat metabolism and energy use. Moreover, SAM is the main donor of the methyl groups needed for these processes.
• When NNMT activity is high, it depletes the levels of SAM. This disrupts the activation of genes that stimulate metabolic function, leading to slower metabolism and fat accumulation.
• Inhibiting NNMT with compounds like 5-Amino-1MQ can upregulate the expression of metabolism-stimulating genes, thereby leading to reduced fat mass, improved insulin sensitivity, and other metabolic benefits.

For example, a study in diet-induced obese mice reported that 5-Amino-1MQ combined with a lean diet led to significant weight and fat loss, improved the ratio of lean mass to body weight, and reduced liver and fat tissue weights, outperforming the effects of a lean diet alone.

Additionally, this combined treatment normalized body composition and liver fat to levels similar to control mice on a lean diet, and induced a distinctive metabolomic profile in adipose tissue, suggesting beneficial alterations in energy metabolism and potential as a therapy for obesity [58].

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Tesofensine

Tesofensine (NS2330) is another non-peptide compound that boasts over 90% oral bioavailability.

It is a selective serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs. In other words, Tesofensine prevents the reuptake of these neurotransmitters and increases their levels in the brain.

As a result, the compound can lead to significant suppression of appetite, but also side effects like dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia [59].

Tesofensine was initially developed in the 1990s by the Danish pharmaceutical company NeuroSearch, as a potential treatment for neurological disorders such as Alzheimer's disease and Parkinson's disease.

The compound turned out to be mostly ineffective for these indications, but the researchers noticed significant weight loss among the study participants, especially those who were overweight or obese [60].

This has led to the investigation of Tesofensine as a weight loss medication by a company called Saniona—a subsidiary of NeuroSearch, and its partner, the Mexican pharmaceutical laboratory Medix.

Following several successful phase 2 studies, the researchers launched a 24-week, randomized, double-blinded, placebo-controlled phase 3 trial that involved 372 participants taking either Tesofensine (0.25 or 0.50mg) or placebo.

Tesofensine was significantly more effective than placebo at both doses, and the majority of participants lost more than 10% of baseline body weight. Further, the average weight loss from baseline during the study period was 10% for the treatment groups [61]. Today, Tesofensine remains one of the most popular weight loss peptides sold by reputable peptides manufacturers.

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Peptides Side Effects and Safety

The weight loss peptides mentioned in this article have each been clinically tested, and the available data consistently show their favorable safety profiles.

For example, the FDA has approved all three of the listed incretin mimetics — semaglutide, tirzepatide, and liraglutide — for human use based on extensive clinical trial data.

Nevertheless, these compounds are not free of side effects. More specifically, the data report that gastrointestinal (GI) side effects are most common with incretin mimetics and include:

• Nausea
• Diarrhea
• Abdominal pain
• Constipation
• Vomiting

According to data, these reactions develop in 40–70% of study volunteers, and rarely up to 85%. Yet, they appear to be transitory and mild to moderate in severity. Serious reactions such as pancreatitis and cholelithiasis are much rarer and affect less than 2% of subjects [62].

Incretin mimetics are contraindicated for use in pregnancy and lactation, as well as in subjects with a history of thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN-2). This is because test animal data report a risk of thyroid neoplasms, although that risk has not been corroborated in humans [1, 63, 64].

Tesamorelin has also been shown as safe according to clinical trial data, which have led to its FDA approval [65]. Common side effects include:

• Injection site reactions (24.5%)
• Peripheral edema (6.1%)
• Worsened glycemic control (4.5%)
• Local allergic reactions (3.6%)

Tesamorelin is contraindicated in subjects with a history of malignancies, as the increase in GH levels stimulates cell proliferation.

AOD-9604 is another peptide with a favorable safety profile, although it is not approved by the FDA for any use [52]. Possible side effects according to data include:

• Nasopharyngitis: 46.8%
• Headache: 30.1%
• Back pain: 25.5%
• Diarrhea: 22.9%

Yet, adverse reactions occurred as frequently in placebo groups according to the data available, so the effects listed above may be unrelated to the peptide.

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Results of Peptide-Based Weight Loss Studies

Below is our review of the most notable peptide-based weight loss studies that report the highest body weight reduction among study volunteers.

Moreover, the majority of the body weight reduction reported by studies with weight loss peptides appears to be attributed to shedding excess fat.

Here are some of the most notable trials to support this:

• Tirzepatide for weight loss: Tirzepatide was recently approved as a weight loss agent following impressive results from the SURMOUNT program. The most extensive trial, encompassing 2,539 adults, demonstrated a weight reduction of 20.9% from baseline after 72 weeks of 15mg/weekly tirzepatide, compared to a 3.1% reduction with placebo. Notably, 91% of those receiving the maximum dosage lost at least 5% of their weight [5, 31, 32].
• Tirzepatide for fat loss: Tirzepatide's fat burning potential was investigated in a substudy of the SURPASS program in Japanese patients with T2D. 15mg/weekly tirzepatide led to an average weight loss of 19.40lb within 12 months from an initial weight of 187.17lb, translating to a 10.4% reduction. The patients exhibited a decline of 5lb in lean mass and 14.55lb in fat mass, indicating improved body composition, with a ~5% decrease in body fat percentage and a 6.1% increase in lean mass [66].
• Semaglutide for weight loss: Semaglutide has received FDA approval for weight loss based on findings from the ongoing STEP program, which comprises several phase 3 trials administering semaglutide at 2.4mg/weekly. Published trials have mainly included individuals with a BMI of at least 30 or at least 27 with associated health issues like T2D. Results indicated a weight reduction of 9.6%-17.4% from the starting weight over 68 weeks at the 2.4mg/weekly dose [8, 36].
• Semaglutide and fat loss: In the STEP 1 trial that included 1961 nondiabetic subjects, the researchers also utilized dual-energy X-ray absorptiometry (DEXA) scans on 140 of the volunteers to investigate the ratio of lean mass and fat loss compared to total weight loss. Semaglutide for these patients resulted in a -32.2lb weight reduction including -18.41lb of fat and -11.58lbs in lean mass. The semaglutide group’s lean mass increased by 3.8% while body fat dropped by 3.0% [67, 68].
• Liraglutide for weight loss: In the Liraglutide SCALE Obesity and Prediabetes trial, 3731 participants without T2D but with a BMI of 30+ (or 27+ with conditions like dyslipidemia or hypertension) were studied. Over 56 weeks, the liraglutide group lost an average of 18.5lb (roughly 8%). By contrast, the placebo group lost an average of 6.2lb (around 2.6%). Significantly, 63.2% of liraglutide recipients achieved at least a 5% weight reduction [69].
• Tesamorelin for fat loss: Tesamorelin, administered at 2mg/daily for 52 weeks, resulted in a 3.7lb decrease in body fat in obese but otherwise healthy study participants. The patients also experienced an 8% reduction in visceral fat from baseline, which was also 19% lower when compared to placebo. In HIV/AIDS patients, tesamorelin has demonstrated up to a 25% reduction in visceral fat within the same timeframe [26, 70].
• AOD-9604 for weight loss: In a 12-week trial, individuals given 1mg/daily AOD-9604 lost an average of 5.72lb, whereas the placebo group lost about 1.76lb. Notably, weight loss was not amplified at the higher 10mg/daily dose of AOD-9604 [22].
• AOD-9604 and fat loss: AOD-9604 induces weight reduction, predominantly due to fat loss, as evidenced in animal studies. In one study, obese Zucker rats exhibited a 50% weight decrease over 19 days and a 23% rise in fat breakdown, as indicated by glycerol release from adipose tissue [71].

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Weight Loss and Peptides | Verdict

The most actively researched peptides for weight loss are tirzepatide, semaglutide, liraglutide, tesamorelin, and AOD-9604.

They appear to work via various mechanisms, including appetite suppression and triggering fat breakdown in specific areas of adiposity.

The majority of these peptides have been FDA approved for weight loss in various patient populations. They are generally available for purchase by qualified researchers for use in educational and experimental settings.

Researchers looking for high-quality peptides for weight loss research are advised to visit our top recommended vendor.

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