10 Peptides For Weight Loss | Ultimate Guide

The popularity of peptides like semaglutide and liraglutide for weight loss has turbocharged interest in the field. Originally developed for the treatment of diabetes, these peptides for fat loss have proved exceptionally efficacious. People the world over are researching the best peptides for weight loss as well as peptides for cutting and other fitness uses. Here is a look at some of the best peptides for weight loss with an emphasis on peptides that burn fat and help to increase lean body mass. 

What Are Peptides for Weight Loss? 

Peptides for weight loss include any small proteins that have been shown to help burn fat or encourage the development of a leaner physique. Research in animals has revealed that there are five different categories of peptides for weight loss, each acting via a different mechanism or on a different receptor. The classes are discussed, and the most representative members of those classes are mentioned.  

It is important to note that the mechanisms vary between different peptides for weight loss and that this can be used to advantage depending on the reason that weight loss is desired. For instance, growth hormone-releasing hormone analogues are beneficial when weight loss is desired but lean body mass preservation is also important. These would fall nicely into peptides for cutting. Alternatively, GLP-1 analogues are peptides that burn fat and help to lower blood sugar. These peptides would be a more suitable choice when blood sugar control is just as important as weight loss. Knowing the various categories and both the primary and secondary effects of the peptides in those categories can be important for making an informed, well-reasoned decision. 

Growth Hormone-Releasing Hormone Analogues 

The growth hormone-releasing hormone (GHRH) analogues are among the oldest of the synthetic peptide hormones in research. Peptides like sermorelin, tesamorelin, and CJC-1295 are some of the most heavily researched and well-understood peptides in the field. 

That GHRH analogues are among the best peptides for weight loss is without dispute. What makes them so potent is that they target fat while building muscle and bone. If ever there were a class of peptides for cutting, the GHRH analogues would be it. 

All the GHRH analogues are excellent at promoting weight loss because they all increase GH levels significantly. Sermorelin and CJC-1295 are also recognized for their ability to boost muscle growth rather substantially. Not only do these peptides directly increase fat metabolism, but the increase in muscle mass that they lead to increases basal metabolism. This means that more calories are burned at rest by the greater muscle mass and thus keeping weight down is easier moving forward. The GHRH analogues are among the handful of peptides that produce effects that make it less likely they will be needed again in the future if diet and exercise remain relatively unchanged.  

Tesamorelin is a slightly different animal to peptides like sermorelin. Tesamorelin is FDA approved for the treatment of lipodystrophy associated with HIV. This condition, which causes abnormal and excessive fat deposition, was nearly impossible to treat before the arrival of tesamorelin on the market. Tesamorelin works by binding to the GHRH receptor and has trans-3-hexanoic acid added to it to preserve its plasma half-life. The peptide has been shown to reduce adiposity by nearly 20% in the target population[1]. 

Before closing the discussion on GHRH analogues, it is important to note the class of peptides that are derived from them. AOD9604 is one such peptide that was originally developed as an anti-obesity research tool. AOD9604 is made up of a small fraction of the GHRH protein known to increase fat burning. It does not stimulate the building of lean body mass like more complete GHRH analogues do. Research shows that administering AOD9604 in animal models can triple weight loss over a 12-week period[2], [3]. It isn’t clear how this peptide works, as it does not directly stimulate the GHRH receptor. It has been speculated that AOD9604 may trigger apoptosis in white fat cells just as Adipotide (see later) does. 

Ghrelin Analogues 

Ghrelin is widely referred to as the hunger hormone and is known to stimulate appetite. What is more, the peptide has also been shown to decrease brown fat thermogenesis (i.e. reduce basal metabolic rate)[4]. Thus, it may not make a lot of sense to think of ghrelin analogues, like ipamorelin, as being among the best peptides for weight loss. As it turns out, however, there are ways in which to use ghrelin analogues like GHRP-6, GHRP-2, and hexarelin to promote weight loss because these peptides favor lean body mass over fat mass. 

Achieving weight loss with peptides like ipamorelin requires intelligent use of the peptides to ensure that calorie deficits exceed calorie consumption. Remember that ghrelin analogues are potent growth hormone secretagogues and GH favors muscle and bone building along with fat burning. If calories consumed remain below expenditure and are from food sources which are high in protein and fiber, then ghrelin analogues can be highly effective peptides for weight loss. Even without the right dietary conditions, animal studies suggest that an increase of almost 9% in muscle mass and a decrease of 14% in fat mass can be expected[5], [6]. 

GLP-1 Analogues – Semaglutide and Liraglutide  

The GLP-1 analogues like semaglutide and liraglutide might just be among the most effective peptides for weight loss on the market right now. They have been the topic of much media attention not just for their weight loss effects, but because their weight loss effects are so profound that they are in short supply. Clinical studies have shown that treatment with GLP-1 receptor agonists, such as liraglutide and semaglutide, is associated with significant and sustained weight loss in obese individuals and those with type 2 diabetes. In fact, higher doses of semaglutide have been specifically developed and approved as a once-weekly injectable medication for chronic weight management. The exact mechanisms by which GLP-1 receptor agonists induce weight loss are not fully understood, but they are believed to involve multiple factors. These include decreased appetite and food intake, delayed gastric emptying, increased energy expenditure, and improvements in insulin sensitivity. 

The first mechanism of appetite suppression for the GLP-1 analogues is through central satiety signaling. Research in mouse models shows that GLP-1 actually reduces the drive to eat and inhibits consumption[7]. When GLP-1 is administered centrally (directly into the central nervous system) to rats, it leads to a significant increase in the expression of c-Fos protein in the supraoptic nucleus, paraventricular nucleus of the hypothalamus (PVN), and central nucleus of the amygdala. The activation pattern of c-Fos is consistent with the appetite-suppressing effects of GLP-1. In other words, GLP-1 analogues like semaglutide activate the neural circuits in the brain that tell us we are full[8]. 

The second mechanism of weight control for GLP-1 analogues is to slow down digestion. When semaglutide is administered, it has several effects on the digestive system. One of these effects is the inhibition of gastric emptying, which means that food stays in the stomach for a longer period before moving into the small intestine. By slowing down gastric emptying, GLP-1 helps to regulate the rate at which nutrients are absorbed from the gastrointestinal tract. This can contribute to increased feelings of fullness and satiety, as well as a more gradual and controlled release of nutrients into the bloodstream. 

Slowing down digestion also has potential benefits for managing blood sugar levels. By delaying the entry of glucose into the bloodstream, GLP-1 can help to prevent sharp spikes in blood sugar after meals, which is particularly relevant for individuals with diabetes or impaired glucose tolerance. Keeping glucose levels from spiking has long been known to help prevent weight gain. This is why nutritionists and dieticians preach the avoidance of “high glycemic index foods.” Semaglutide is among the best peptides for weight loss because it essentially forces the body to slow down absorption and thus reduces the glycemic index of all foods. 

A third mechanism of weight control for GLP-1 analogues is to increase basal energy expenditure. Research in mice indicates increased expression of UCP-1 and UCP-3 in brown fat along with inhibition of acetyl-CoA carboxylase in skeletal muscle. Both findings indicated increased fatty acid oxidation and thermogenesis. In short, semaglutide forces the body to “waste” energy by increasing metabolism and generating heat. This higher level of metabolism means increased calorie burn, even at rest. GLP-1 has been found to influence not just metabolic rate, but substrate utilization as well. Research suggests that GLP-1 may enhance lipid oxidation (fat burning) and improve mitochondrial function, leading to increased energy expenditure.[8]. In other words, GLP-1 analogues primarily target adipose tissue when they increase energy use. This is why semaglutide is one of the best peptides that burn fat.  

The final mechanism of weight control for GLP-1 analogues, is the primary mechanism for which they were developed. Semaglutide, liraglutide, and other GLP-1 analogues increase insulin sensitivity. Increased insulin sensitivity means that less insulin is needed to get a given quantity of glucose into muscle, fat, and liver tissue.  

The connection between insulin and adiposity isn’t all that clear. Research shows that high insulin sensitivity is associated with reduction in visceral fat and weight[9]. Interestingly, it is the brain’s insulin sensitivity that plays the bigger role in weight control, suggesting that fat deposition is as much controlled by the central nervous system as it is by peripheral hormone levels. Having said all of that, however, insulin is a primary driver of fat deposition, so it isn’t entirely clear if increased sensitivity is the best way to promote weight loss. It is, however, the best way to promote long-term good health and avoid the scourge of diabetes. 

GLP-1 and GIP Analogues - Tirzepatide 

GLP-1 is just one of two different incretins that are naturally produced by the body. Incretins are a group of hormones that play a significant role in regulating blood sugar levels in the body. They are primarily produced and released by specialized cells in the gastrointestinal tract in response to the ingestion of food. The two main incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).  

GLP-1 agonists mimic the effects of glucagon-like peptide-1 and bind to receptors for GLP-1 are found on the surface of pancreatic beta cells of the pancreas, in the intestines, on the vagus nerve, and in the brain. GIP agonists mimic the effects of gastric inhibitory peptide (GIP). GIP got its name from its earliest known effect, which is the inhibition of release of stomach acid. It turns out, however, that this is not a native effect of GIP and that the peptide only inhibits stomach acid when used in supraphysiologic doses[10]. Like many peptides, GIP was named incorrectly because of poor research, but the name has stuck. 

At physiologic doses, GIP plays an important role in the induction of insulin secretion secondary to glucose consumption. Researchers now refer to the peptide as glucose-dependent insulinotropic peptide and retain the GIP acronym. Either name is considered acceptable in research circles, but it is always a good idea to clarify just to be certain. 

The best-known GIP analogue currently is Tirzepatide . Approved for the once-weekly treatment of obesity and for the treatment of diabetes, Tirzepatide has shown enhanced efficacy over strict GLP-1 analogues like semaglutide. Research has shown that once-weekly administration produces reductions in body weight of 20% or more at 72 weeks. Some test participants lost one third of their body weight by the end of the trial. The peptide also leads to improvements in cardiometabolic measures such as reduced blood pressure, improved fasting insulin levels, lower lipid levels, and so forth[11]. 

What makes Tirzepatide so efficacious is that it binds to both GLP-1 and GIP receptors. GLP-1 and GIP are very closely related, being slight variants of the same pro-peptide that is modified during release from the intestine. As such, scientists were able to design a synthetic analogue that could bind to both GLP-1 and GIP receptors. While GLP-1 is considered the more efficacious of the two molecules in normal physiology, a peptide like Tirzepatide that can do the job of both has enhanced effects. One needs only to look at the massive 20-33% weight loss Tirzepatide produced in phase 3 clinical trials to see that the peptide is superior to strict GLP-1 analogues. Tirzepatide has superior effects on appetite suppression as well as blood sugar reduction. After injection, it has a bioavailability of roughly 80% and a half-life of 5 days[12]. 

Melanocortin Analogues – Melanotan-2 

Melanocortins, specifically melanocortin receptor agonists, have been investigated for their potential effects on weight loss and appetite regulation. The melanocortin system plays a role in the regulation of energy balance, including food intake and energy expenditure. Melanocortin peptides, such as α-melanocyte-stimulating hormone (α-MSH), act on melanocortin receptors located in the brain, particularly the melanocortin-4 receptor (MC4R). Activation of MC4R is believed to suppress appetite and increase energy expenditure, potentially leading to weight loss[13]. 

Studies in mouse and rat models suggest that Melanotan 2, through its interaction with melanocortin receptors, can have several effects that contribute to weight loss. First, the binding of Melanotan 2 to melanocortin receptors, particularly the melanocortin-4 receptor (MC4R), appears to reduce food intake and alter food preferences, leading to decreased total food consumption and reduced preference for fatty foods in mouse models[14]. 

Research also shows that activation of the melanocortin system has been associated with significant and sustained reductions in body mass in mice without imposing long-term calorie restriction[15]. This suggests that Melanotan 2 may have long-term effects on energy balance regulation and supports the findings above suggesting that melanocortin activation can reduce food intake and alter food preferences. 

Interestingly, Melanotan 2 does not only alter energy intake as a means of controlling energy balance. Research in rats shows that it can increase uncoupling protein 1 messenger RNA, which can induce weight loss by promoting energy expenditure[16]. Uncoupling protein 1 works to divorce the expenditure of energy from its use in cell growth and development. Thus, energy that would normally be used for cell growth is simply wasted when there is more uncoupling protein 1 present. This takes place primarily in fatty tissue, so increasing the amount of this protein leads to a reduction in adiposity. This may be the mechanism by which Melanotan 2 leads to weight loss without a change in calorie intake. It would also explain why, in animal studies, Melanotan 2 has been a stand-out among peptides that burn fat. 

Bremelanotide, which is very similar in sequence and structure to Melanotan 2, has shown similar abilities. While studies have suggested that existing melanocortin peptides may have an impact on appetite regulation and energy expenditure, there is interest in developing more weight-specific melanocortin peptides. Such peptides would be developed to target the MC4R without affecting any other receptors. This would lead to a reduction in side effects and may also increase the fat burning capabilities of these peptides. The melanocortin system is relatively poorly understood, however, and the specificity of each receptor is in question. Thus, whether it is feasible to develop a highly specific melanotan peptide for fat loss remains to be tested. 

Adipotide 

Adipotide gets its own category because it is unique among the fat-loss peptides. Developed around 2011, Adipotide targets and kills fat cells. It accomplishes this feat by cutting off the blood supply to these cells and these cells only[17]. Research in monkeys shows that treatment with Adipotide and subsequent fat loss do not only improve weight, but can decrease the drive to eat[18]. This is likely because fat cells actually stimulate further fat production by releasing a peptide called neuropeptide Y. NPY, as it is abbreviated, is the most potent stimulator of appetite that is known[19]. Thus, the more fat we have, the more NPY we produce and the hungrier we feel. By increasing fat burning, Adipotide helps to overcome this barrier and, over time, decreases feelings of hunger. 

Tesofensine 

Though not a peptide at all, Tesofensine deserves brief mention among the classes of peptides for weight loss. This serotonin-norepinephrine-dopamine reuptake inhibitor is in phase III trials for the treatment of obesity. It isn’t entirely clear how Tesofensine works to induce weight loss, but studies support its role in this regard. Scientists speculate that tesofensine affects appetite control and energy expenditure by altering neurotransmitter reuptake. Research shows that tesofensine increases weight loss more than 2-fold over diet and exercise changes alone[20]. 

Conclusion 

As the reader can see, there are a great number of peptides for weight loss. Which peptides are right for a given application, however, comes down to several factors. If the goal is to simply burn fat, the Adipotide offers a very targeted approach. For the control of blood sugar in combination with weight loss, GLP-1 analogues like semaglutide might be the right way to go. The best peptides for cutting are, however, the GHRH analogues. 

Weight loss is a complex process that scientists are learning has less to do with will power than it has to do with a person’s unique biochemical state. Peptides for weight loss are just the latest (and perhaps most successful) approach to manipulating that biochemical state to help enhance weight loss. The future is likely to hold a lot of surprises in the weight loss field; it certainly holds a lot of promise. 

Resources 

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[2] “Obesity drug codenamed AOD9604 highly successful in trials,” News-Medical.net, Dec. 16, 2004. https://www.news-medical.net/news/2004/12/16/6878.aspx (accessed Sep. 17, 2022). 

[3] R. Zieba, “[Obesity: a review of currently used antiobesity drugs and new compounds in clinical development],” Postepy Hig. Med. Doswiadczalnej Online, vol. 61, pp. 612–626, Oct. 2007. 

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[5] P. B. Johansen, Y. Segev, D. Landau, M. Phillip, and A. Flyvbjerg, “Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue,” Exp. Diabesity Res., vol. 4, no. 2, pp. 73–81, Jun. 2003, doi: 10.1155/EDR.2003.73. 

[6] R. G. Smith and M. O. Thorner, Human Growth Hormone: Research and Clinical Practice. Springer Science & Business Media, 2000. 

[7] M. Tang-Christensen, P. J. Larsen, J. Thulesen, J. Rømer, and N. Vrang, “The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake,” Nat. Med., vol. 6, no. 7, pp. 802–807, Jul. 2000, doi: 10.1038/77535. 

[8] M. Tang-Christensen, N. Vrang, and P. J. Larsen, “Glucagon-like peptide containing pathways in the regulation of feeding behaviour,” Int. J. Obes. Relat. Metab. Disord. J. Int. Assoc. Study Obes., vol. 25 Suppl 5, pp. S42-47, Dec. 2001, doi: 10.1038/sj.ijo.0801912. 

[9] “Brain insulin sensitivity determines body weight and fat distribution,” ScienceDaily. https://www.sciencedaily.com/releases/2020/04/200424132612.htm (accessed Jun. 15, 2023). 

[10] W. Kim and J. M. Egan, “The role of incretins in glucose homeostasis and diabetes treatment,” Pharmacol. Rev., vol. 60, no. 4, pp. 470–512, Dec. 2008, doi: 10.1124/pr.108.000604. 

[11] A. M. Jastreboff et al., “Tirzepatide Once Weekly for the Treatment of Obesity,” N. Engl. J. Med., vol. 387, no. 3, pp. 205–216, Jul. 2022, doi: 10.1056/NEJMoa2206038. 

[12] K. Farzam and P. Patel, “Tirzepatide,” in StatPearls, Treasure Island (FL): StatPearls Publishing, 2023. Accessed: Jun. 16, 2023. [Online]. Available: http://www.ncbi.nlm.nih.gov/books/NBK585056/ 

[13] A. S. Garfield et al., “A neural basis for melanocortin-4 receptor–regulated appetite,” Nat. Neurosci., vol. 18, no. 6, Art. no. 6, Jun. 2015, doi: 10.1038/nn.4011. 

[14] T. H. Meek, M. E. Matsen, V. Damian, A. Cubelo, S. C. Chua, and G. J. Morton, “Role of Melanocortin Signaling in Neuroendocrine and Metabolic Actions of Leptin in Male Rats With Uncontrolled Diabetes,” Endocrinology, vol. 155, no. 11, Art. no. 11, Nov. 2014, doi: 10.1210/en.2014-1169. 

[15] C. I et al., “Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction,” Can. J. Physiol. Pharmacol., vol. 95, no. 2, Feb. 2017, doi: 10.1139/cjpp-2016-0290. 

[16] M. M. Glavas, S. E. Joachim, S. J. Draper, M. S. Smith, and K. L. Grove, “Melanocortinergic activation by melanotan II inhibits feeding and increases uncoupling protein 1 messenger ribonucleic acid in the developing rat,” Endocrinology, vol. 148, no. 7, pp. 3279–3287, Jul. 2007, doi: 10.1210/en.2007-0184. 

[17] M. G. Kolonin, P. K. Saha, L. Chan, R. Pasqualini, and W. Arap, “Reversal of obesity by targeted ablation of adipose tissue,” Nat. Med., vol. 10, no. 6, pp. 625–632, Jun. 2004, doi: 10.1038/nm1048. 

[18] K. F. Barnhart et al., “A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys,” Sci. Transl. Med., vol. 3, no. 108, Art. no. 108, Nov. 2011, doi: 10.1126/scitranslmed.3002621. 

[19] “Your Belly Fat Could Be Making You Hungrier,” ScienceDaily. https://www.sciencedaily.com/releases/2008/04/080416153551.htm (accessed Jun. 15, 2023). 

[20] A. Astrup, S. Madsbad, L. Breum, T. J. Jensen, J. P. Kroustrup, and T. M. Larsen, “Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial,” Lancet Lond. Engl., vol. 372, no. 9653, Art. no. 9653, 29 2008, doi: 10.1016/S0140-6736(08)61525-1. 

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