Best Peptides for Fat Loss in 2026: Evidence-Based Rankings

Overview

Fat loss — the specific reduction of adipose tissue while preserving lean mass — represents a more nuanced goal than total weight loss and involves distinct biological mechanisms. While GLP-1 receptor agonists produce dramatic total weight loss, a meaningful fraction (25-40%) of weight lost may be lean tissue. This ranking evaluates peptides specifically through the lens of fat loss and body composition improvement, considering not just total weight reduction but the ratio of fat-to-lean mass change where such data is available. Compounds are ranked by the strength of evidence demonstrating selective fat reduction, metabolic rate enhancement, or adipose tissue-specific mechanisms. Some peptides on this list overlap with those on weight loss rankings but are evaluated here for their fat-specific properties rather than total body weight effects. This article is educational only and does not constitute medical advice. Body composition management should involve a qualified healthcare provider.

How We Ranked These Peptides

This ranking is based on four criteria applied consistently across every compound: (1) the quality and size of available human clinical evidence, (2) the specificity of the mechanism to fat loss, body fat reduction, and improved body composition, (3) the current regulatory and approval status, and (4) the reproducibility of reported outcomes. Peptides backed by large randomized controlled trials rank above those with only phase 2 data, which in turn rank above compounds supported only by animal studies or anecdotal reports. This hierarchy is not a recommendation — it is an evidence-quality snapshot designed to help readers distinguish well-studied compounds from speculative ones. Individual suitability depends on medical history, contraindications, and the guidance of a qualified healthcare provider.

How Peptides Influence Fat Loss

Peptides affect fat metabolism through several distinct pathways. GLP-1 and GIP receptor agonists reduce caloric intake through appetite suppression and delayed gastric emptying, producing fat loss as part of overall caloric deficit — though lean mass loss is also significant. Growth hormone-releasing peptides promote lipolysis (fat breakdown) and may shift body composition toward greater lean mass retention. Some peptides target adipose tissue directly: tesamorelin stimulates endogenous GH to mobilize visceral fat, AOD-9604 was designed to isolate the fat-metabolizing fragment of growth hormone, and 5-Amino-1MQ inhibits NNMT to alter fat cell energy metabolism. MOTS-c acts as a mitochondrial peptide that enhances fatty acid oxidation at the cellular level. The ideal fat loss peptide would maximize adipose tissue reduction while minimizing lean mass catabolism — a balance that current compounds achieve to varying degrees.

#1: Semaglutide (Wegovy) (FDA-Approved)

Semaglutide produces substantial total weight loss, but its fat loss profile deserves specific examination. DEXA body composition analysis from the STEP trials indicates that approximately 60-75% of total weight lost with semaglutide is fat mass, with the remainder being lean tissue. At 14.9-16.9% total weight loss, this translates to roughly 9-13% body fat reduction. While the absolute fat loss is significant, the concurrent lean mass loss has prompted research into combining semaglutide with resistance training to improve the fat-to-lean loss ratio. Semaglutide's mechanism is primarily appetite-driven caloric deficit rather than direct fat metabolism modulation, which partly explains why lean tissue is also affected. For individuals whose primary goal is fat-specific reduction, this composition of weight loss is an important consideration.

• Evidence level: Strong — FDA-approved with extensive phase 3 RCT data including DEXA body composition measurements in substudies
• Key finding: The STEP 1 trial demonstrated 14.9% total weight loss at 68 weeks, with body composition analysis indicating approximately 60-75% of weight lost was fat mass and 25-40% was lean tissue
• Mechanism: GLP-1 receptor agonist that reduces caloric intake through appetite suppression and delayed gastric emptying, producing fat loss primarily through sustained caloric deficit
• Administration: Once-weekly subcutaneous injection with gradual dose escalation
• Regulatory status: FDA-approved for chronic weight management (Wegovy) and type 2 diabetes (Ozempic)
• Key consideration: Significant lean mass loss alongside fat loss may be suboptimal for individuals focused on body composition rather than total weight — resistance training may help preserve lean mass during treatment

#2: Tirzepatide (Zepbound) (FDA-Approved)

Tirzepatide has produced the highest fat loss of any FDA-approved medication in clinical trials. Body composition data from the SURMOUNT program suggests that tirzepatide may produce a more favorable fat-to-lean loss ratio compared to semaglutide, though direct head-to-head composition data is limited. At up to 22.5% total weight loss, even with 25-35% lean mass contribution, the absolute fat mass reduction is substantial. The dual GIP/GLP-1 mechanism may contribute to somewhat better lean mass preservation compared to GLP-1-only agonists, as GIP receptor activation has been linked to effects on adipocyte biology and lipid metabolism that are distinct from appetite suppression alone. For body composition-focused fat loss, tirzepatide currently represents the most effective FDA-approved option.

• Evidence level: Strong — FDA-approved with phase 3 RCT data; emerging body composition data suggesting favorable fat-to-lean loss ratios
• Key finding: The SURMOUNT-1 trial demonstrated up to 22.5% total weight loss at 72 weeks, with body composition analyses suggesting that the dual GIP/GLP-1 mechanism may produce comparatively better lean mass preservation than GLP-1-only agonists
• Mechanism: Dual GIP/GLP-1 receptor agonist that reduces caloric intake while potentially influencing adipocyte metabolism and lipid handling through the GIP receptor component
• Administration: Once-weekly subcutaneous injection with dose escalation from 2.5 mg to a maximum of 15 mg
• Regulatory status: FDA-approved for weight management (Zepbound) and type 2 diabetes (Mounjaro)
• Key consideration: The GIP receptor component may provide body composition advantages over GLP-1-only agonists, but definitive head-to-head body composition data is still accumulating

#3: Retatrutide (Investigational)

Retatrutide's triple receptor mechanism (GIP/GLP-1/glucagon) is particularly relevant for fat loss because the glucagon receptor component directly increases hepatic energy expenditure and fat oxidation — mechanisms that specifically target fat metabolism rather than simply reducing caloric intake. In phase 2 trials, retatrutide produced up to 24.2% total weight loss at 48 weeks, and the glucagon component may contribute to a higher proportion of fat loss relative to lean mass. Glucagon receptor activation increases lipolysis, fatty acid oxidation, and thermogenesis, providing an active fat-burning effect that complements the appetite suppression from GIP and GLP-1 receptor activation. This multi-mechanism approach makes retatrutide one of the most promising compounds for fat-specific body composition improvement, though phase 3 data is still pending.

• Evidence level: Strong phase 2 data; awaiting phase 3 confirmation; glucagon receptor component provides a mechanistically distinct fat-burning pathway
• Key finding: Phase 2 trials showed 24.2% total weight loss at 48 weeks, with the glucagon receptor component expected to enhance fat oxidation and energy expenditure beyond what GLP-1 agonism alone achieves
• Mechanism: Triple GIP/GLP-1/glucagon receptor agonist — the glucagon component specifically increases hepatic fatty acid oxidation, lipolysis, and thermogenesis to promote preferential fat loss
• Administration: Once-weekly subcutaneous injection in clinical trial protocols
• Regulatory status: Investigational — phase 3 TRIUMPH program ongoing; not available for purchase or prescription
• Key consideration: The glucagon receptor component is what distinguishes retatrutide for fat-specific applications, but also introduces potential effects on blood glucose that require monitoring

#4: Tesamorelin (Egrifta) (FDA-Approved for Visceral Fat)

Tesamorelin is uniquely relevant for fat loss because it is the only peptide on this list FDA-approved specifically for a fat reduction indication — visceral adipose tissue reduction in HIV-associated lipodystrophy. Its mechanism through growth hormone axis stimulation promotes lipolysis while potentially preserving or even increasing lean mass, making it mechanistically distinct from caloric-deficit-based approaches. Clinical trials demonstrated 15-18% visceral fat reduction without the significant lean mass loss seen with GLP-1 agonists. In fact, some studies have shown modest increases in lean body mass concurrent with visceral fat reduction. This body composition profile — fat loss with lean mass preservation — is particularly appealing for individuals focused on body recomposition rather than total weight reduction.

• Evidence level: Strong for visceral fat reduction in its approved indication; moderate for general body composition improvement
• Key finding: A 2010 clinical trial demonstrated that tesamorelin reduced visceral adipose tissue by 15-18% at 26 weeks while preserving or modestly increasing lean body mass, producing favorable body composition changes
• Mechanism: GHRH analog that stimulates endogenous pulsatile GH release, promoting lipolysis (particularly in visceral adipose depots) while supporting lean mass through GH-mediated protein synthesis
• Administration: Daily subcutaneous injection
• Regulatory status: FDA-approved for reduction of excess abdominal fat in HIV-infected patients with lipodystrophy (Egrifta); off-label use for general body composition in some clinical settings
• Key consideration: Tesamorelin produces more modest total weight change than GLP-1 agonists but with a more favorable fat-to-lean ratio — its value is in body composition improvement rather than scale weight reduction

#5: AOD-9604

AOD-9604 was specifically designed for fat loss — it is a synthetic fragment of growth hormone (amino acids 177-191) intended to replicate the fat-metabolizing properties of GH without its growth-promoting or diabetogenic effects. In preclinical studies, AOD-9604 stimulated lipolysis and inhibited lipogenesis through beta-3 adrenergic receptor pathways. The compound reached phase 2 clinical trials for obesity, where it showed some evidence of fat reduction, though results were not robust enough to advance to phase 3. Importantly, AOD-9604 did not significantly affect IGF-1 levels, insulin sensitivity, or glucose tolerance in clinical studies, supporting its design goal of isolating the fat-specific effects of GH. Despite stalled clinical development, AOD-9604 remains one of the most discussed fat loss peptides in clinical practice settings.

• Evidence level: Moderate — phase 2 human data available showing fat reduction without IGF-1 or insulin effects; clinical development stalled after phase 2
• Key finding: Phase 2 trials demonstrated that AOD-9604 stimulated fat loss without affecting IGF-1 levels, insulin sensitivity, or glucose tolerance, supporting its mechanism as a targeted fat-metabolizing GH fragment
• Mechanism: Growth hormone fragment (amino acids 177-191) that stimulates lipolysis and inhibits lipogenesis through beta-3 adrenergic pathways without activating the IGF-1 axis or affecting insulin sensitivity
• Administration: Subcutaneous injection in clinical trial and practitioner settings
• Regulatory status: Not FDA-approved; clinical development for obesity did not advance past phase 2; available through some compounding pharmacies and research suppliers
• Key consideration: The targeted mechanism (fat metabolism without GH-like growth effects) is appealing in theory, but the failure to advance past phase 2 suggests the clinical fat loss effect may be modest

#6: 5-Amino-1MQ (NNMT Inhibitor)

5-Amino-1MQ inhibits nicotinamide N-methyltransferase (NNMT), an enzyme overexpressed in the adipose tissue of obese individuals. NNMT inhibition increases intracellular NAD+ levels, which activates sirtuin-mediated metabolic pathways and promotes the conversion of energy-storing white adipose tissue to metabolically active beige adipose tissue — a process called browning. In animal models, NNMT inhibition reduced body fat, increased energy expenditure, and improved metabolic markers without affecting food intake — suggesting a mechanism that specifically targets fat metabolism rather than appetite. The food intake-independent fat reduction is particularly interesting for body composition, as it implies fat loss without the caloric restriction that also depletes lean mass. However, 5-Amino-1MQ has no published human clinical trial data.

• Evidence level: Preliminary — preclinical animal data demonstrating fat reduction and metabolic improvement without caloric restriction; no human clinical trials
• Key finding: A 2020 study showed that NNMT inhibition in obese mice reduced body fat, increased NAD+ levels, and promoted white-to-beige adipose tissue conversion without reducing food intake — suggesting a direct fat-metabolizing mechanism
• Mechanism: NNMT inhibitor that raises intracellular NAD+ in adipose tissue, activates sirtuin-mediated fat oxidation pathways, and promotes browning of white adipose tissue to increase metabolic rate
• Administration: Oral capsule in practice settings; the oral bioavailability of this small molecule is an advantage over injectable peptides
• Regulatory status: Not FDA-approved; no human clinical trials in progress; sold as a research chemical
• Key consideration: Food intake-independent fat reduction in animal models is promising for body composition, but the complete absence of human data means efficacy, dosing, and safety in humans are unknown

#7: MOTS-c (Mitochondrial Peptide)

MOTS-c is a mitochondrial-derived peptide that functions as an exercise mimetic, activating AMPK to enhance fatty acid oxidation, glucose uptake, and overall cellular energy metabolism. In animal studies, MOTS-c administration prevented diet-induced obesity and improved metabolic parameters including insulin sensitivity and lipid profiles. Its mechanism of action is particularly relevant to fat loss because AMPK activation directly promotes fat oxidation and inhibits fat synthesis at the cellular level. MOTS-c levels decline naturally with age, which correlates with the age-related decrease in metabolic rate and increase in body fat percentage. The exercise-mimetic properties suggest that MOTS-c could enhance fat oxidation in a manner complementary to physical activity. However, all fat loss evidence comes from animal models, and human clinical data for body composition endpoints is not available.

• Evidence level: Preliminary — preclinical animal data demonstrating resistance to obesity and improved fat metabolism; no human clinical trials for fat loss or body composition
• Key finding: A 2015 study demonstrated that MOTS-c activated AMPK, enhanced fatty acid oxidation, and prevented diet-induced obesity in mice, with improved insulin sensitivity and metabolic markers
• Mechanism: Mitochondrial-derived peptide that activates AMPK to enhance fatty acid oxidation, increase glucose uptake, improve mitochondrial function, and mimic the metabolic effects of exercise
• Administration: Subcutaneous injection in animal research protocols
• Regulatory status: Not FDA-approved; classified as a research peptide; very limited human research for any indication
• Key consideration: The exercise-mimetic mechanism is theoretically appealing for fat loss, but age-related MOTS-c decline and the feasibility of supplementation in humans have not been validated in clinical trials

How to Evaluate Fat Loss Peptide Claims

Fat loss peptide claims should be evaluated with attention to the distinction between total weight loss and fat-specific body composition changes. Many compounds produce weight loss through caloric deficit, which necessarily includes lean mass reduction. Peptides that claim fat-specific effects should be supported by body composition data (DEXA, CT) rather than scale weight alone.

• Demand body composition data (DEXA, CT, MRI) rather than scale weight alone — total weight loss does not distinguish between fat and lean mass changes
• Distinguish between caloric deficit-driven fat loss (GLP-1 agonists) and direct fat metabolism mechanisms (tesamorelin, AOD-9604, 5-Amino-1MQ) — these have different implications for lean mass preservation
• Evaluate whether the fat loss observed was visceral (metabolically relevant), subcutaneous, or both — some peptides preferentially target visceral fat
• Consider the fat-to-lean loss ratio as a key metric — a compound producing 22% weight loss with 40% lean mass contribution may be less desirable for body composition than one producing 15% loss with 75% fat composition
• Be cautious of "fat burning" claims from compounds that only have appetite-suppression mechanisms — caloric deficit affects all tissues, not just fat
• Assess whether animal model fat loss results translate to humans — mice have different brown adipose tissue distribution and metabolic scaling
• Consider whether fat loss is maintained after discontinuation — some mechanisms produce durable metabolic changes while others require ongoing administration

Important Safety and Legal Considerations

Fat loss peptides span multiple mechanism classes with distinct safety profiles. GLP-1 agonists have extensive safety databases from large clinical trials, while investigational compounds have minimal human safety data. The metabolic effects of fat-targeting peptides may interact with glucose regulation, lipid metabolism, and hormonal systems.

• FDA-approved GLP-1 agonists (semaglutide, tirzepatide) have well-characterized gastrointestinal side effects that typically diminish with dose titration; rare but serious risks are documented
• Tesamorelin may affect glucose metabolism and is specifically studied in HIV populations — its safety profile in the general population for fat loss is less established
• AOD-9604 did not show significant safety signals in phase 2 trials, but the limited trial duration and size preclude definitive safety conclusions
• NNMT inhibitors (5-Amino-1MQ) alter fundamental cellular energy metabolism — the long-term consequences of chronic NAD+ elevation in adipose tissue are unknown
• MOTS-c affects AMPK signaling, a pathway with broad metabolic implications — unintended effects on muscle, liver, and other tissues have not been evaluated in humans
• Lean mass loss with GLP-1 agonists may include reductions in bone density and muscle mass that have implications for long-term metabolic health and functional capacity
• Medical supervision with regular metabolic panel monitoring is essential for any fat loss peptide protocol, as effects on glucose, insulin, lipids, and hormones should be tracked

Explore Next

References

1. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1) (2021) — PubMed
2. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) (2022) — PubMed
3. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial (2023) — PubMed
4. Tesamorelin for the Treatment of Visceral Adiposity in HIV-Infected Patients (2010) — PubMed
5. AOD9604 — A Novel Anti-Obesity Compound (2001) — PubMed
6. NNMT Inhibition Reduces Body Weight and Improves Metabolic Parameters in Obese Mice (2020) — PubMed
7. The Mitochondrial-Derived Peptide MOTS-c: A Player in Exceptional Longevity? (2015) — PubMed