Obesity is the biggest global health crisis of our time, driving an alarming increase in metabolic disorders like type 2 diabetes non-alcoholic fatty liver disease. GLP-1 receptor agonists, such as semaglutide (you have probably heard of Ozempic), have gained attention for their impressive weight loss results. What’s the catch? The side effects: users are likely to experience gastrointestinal issues (nausea, vomiting, diarrhea) and fatigue. The rapid weight loss can also lead to a loss of muscle mass. Less common but more severe side effects of these drugs include inflammation of the pancreas and gallbladder, as well as kidney issues. Additionally, the potential long-term metabolic effects are still not fully understood. There is just never an easy shortcut to sustainable health! While these drugs can help address obesity concerns in a radical way, there are safer and more sustainable options—like spermidine—that offer a promising natural path to weight management and improved metabolic health. Spermidine can promote fat loss, improve insulin sensitivity and reduce inflammation. Unlike the often-harsh side effects of pharmaceutical options, spermidine represents a more gentle, sustainable, and holistic approach. Let’s dive into the scientific literature.
Spermidine boosts fat burning
An important study published in the Journal of Nutritional Biochemistry (2024) found that spermidine promotes thermogenesis (the production of heat by burning fat) in mice with high-fat diets, improving glucose and lipid metabolism through the activation of autophagy and up-regulation of fibroblast growth factor 21 (FGF21) signaling, a crucial hormone regulating energy expenditure (how your body uses sugar and fat). The study suggests that spermidine's effects on thermogenesis are mediated through FGF21 signaling via the PI3K/AKT (which regulates cell growth and responds to nutrients and growth signals) and AMPK (which regulates energy levels and responds to low energy levels) pathways. This suggests that spermidine can increase fat burning energy expenditure in metabolically stressed environments. Additional studies corroborate this. Previous research in Amino Acids (2013) showed that SSAT, an enzyme involved in polyamine metabolism, plays a critical role in regulating fat accumulation, most likely through the modulation of the AMPK pathway. Similarly, a study from the Journal of Biological Chemistry (2007) found that enhanced SSAT overexpression resulted in leaner phenotypes, while its deletion led to increased fat storage.
Spermidine limits fat accumulation
Several studies have demonstrated the role of spermidine in regulating lipid metabolism. A study published in Medical Sciences (2021)in Drosophila (flies) models found that mutations in spermidine synthase (SpdS, the enzyme that synthesize spermidine) in flies resulted in an increase in triglyceride storage, underscoring spermidine’s role in lipid regulation and its potential in limiting fat accumulation. A study in Molecular Sciences (2022) revealed that spermine, another polyamine, suppressed adipocyte differentiation and fat accumulation in mice on high-fat diets, suggesting it could be a potential treatment for obesity. More evidence comes from a Nature Communications (2021) study, showing that spermidine treatment improved mitochondrial fatty acid oxidation, a vital process in energy metabolism, and prevent the progression of non-alcoholic steatohepatitis (NASH, a type of fatty liver disease) via the now well-known hypusination of the translation factor eIF5A (a key player in triggering autophagy). Similarly, research in Cell Death and Disease (2017) demonstrated that spermidine treatment reduced weight gain, decreased visceral fat, and improved glucose tolerance and insulin sensitivity in mice fed a high-fat diet, thanks to the induction of autophagy.
Spermidine restores gut health and reduces inflammation
Obesity is often linked to gut dysbiosis (an imbalance in the normal healthy community of microorganisms, or gut microbiota, characterized by an overgrowth of pathogenic bacteria and a decline in beneficial bacteria) and chronic inflammation. We know that long-term exposure to Western diets (rich in processed foods and sugar) is a key driver of obesity, with the gut microbiome (the microbiota and the whole environment they create) serving as a crucial intermediate between the two. Since the gut microbiome is the primary source of polyamines in the body, with the highest concentrations found in the intestinal lumen, disruptions in microbial balance due to obesity can lead to dysregulated polyamine synthesis. A comprehensive review published in Frontiers in Endocrinology (2023) summarizes extensive research showing how spermidine can restore gut microbiota balance, reduce metabolic endotoxemia, and enhance immune function. These findings suggest that spermidine holds significant promise as a nutraceutical for mitigating metabolic and immune complications associated with obesity.
A Gut Microbes (2020) study further demonstrated that spermidine supplementation improved gut barrier integrity and increased the population of beneficial short-chain fatty acid (SCFA)-producing bacteria, promoting weight loss and insulin sensitivity in obese mice. Interestingly, the study demonstrated that the beneficial effects of spermidine on obesity were partly mediated by the gut microbiota. When the gut microbiota was depleted using antibiotics, the protective effects of spermidine on obesity were abolished. Conversely, fecal microbiota transplantation from spermidine-treated mice to obese mice conferred similar protective effects against obesity, highlighting the essential role of gut microbiota in mediating the anti-obesity effects of spermidine. A paper published in the Journal of Allergy and Clinical Immunology (2021) further supports the potential of spermidine in regulating immune function, showing that it promotes the differentiation of naive T cells (the immune cells before they are activated by a pathogen) into regulatory T cells (the immune cells that prevent autoimmune reactions) and enhances intestinal homeostasis, offering additional evidence of spermidine’s role in reducing inflammation and promoting immune tolerance.
Proposed health benefits of dietary polyamines in obesity-related diseases. Polyamines ameliorate metabolic syndrome by reducing weight gain, insulin resistance, lipid metabolism, gut barrier function, and metabolic endotoxemia. Polyamines also regulate both innate and adaptive immunity including proinflammatory cytokine production, autophagy, macrophage polarization, T cell differentiation, and B cell senescence. Figure from Bui et al. All rights reserved.
A game changer for type 2 diabetes?
Almost all type 2 diabetes (T2D) cases are linked to obesity. Beyond its role in obesity, spermidine has also shown promise in preventing and managing T2D. A study from the European Journal of Pharmacology (2014) found that spermine administration significantly reduced fasting glucose levels and improved glucose utilization in obese mice. Further supporting spermidine's potential role in improving metabolic health, a study published in Molecular Metabolism suggested that increased levels of spermidine in the blood of mice overexpressing SIRT6 (part of the sirtuin family, referred to as “longevity genes”) were associated with protection against died-induced hyperglycemia and enhanced insulin sensitivity.
While spermidine’s effects are promising and clinical trials on spermidine supplementation are still progressing, further research is needed to determine optimal dosing and efficacy across different populations. A 2024 study in Frontiers in Nutrition found that moderate levels of serum spermidine (meaning levels found in the blood) in humans are associated with lower risk of T2D. The study also found that those levels have a complex, non-linear relationship with T2D, suggesting the need for personalized approaches. Additionally, a 2022 study in Nutrients linked higher serum spermidine levels to a reduced risk of BMI increase over two years in obese patients, indicating a potential protective effect against obesity progression. It is important to note that serum spermidine levels do not necessarily reflect how spermidine is utilized within cells, and there is currently no established correlation between serum, intracellular, and supplement-derived spermidine levels. Therefore, one can easily find inconsistencies in the landscape of studies due to heterogenous methods, tissue sampling and sometimes a lack of control groups. Moreover, since the gut microbiome is the primary driver of polyamine production in the body, serum levels might not be the most relevant parameter to consider when studying T2D. Instead, levels in fecal samples might offer more insight into its role (see this excellent review for a detailed discussion on the topic).
Most evidence suggests that spermidine supplementation plays a protective role, particularly in T2D. This was recently underscored in a groundbreaking study published in Nature Cell Biology, which showed that spermidine plays a significant protection role in T2D by inhibiting necroptosis (programmed cell death with inflammation) through the inactivation of its key regulator RIPK1 and improving insulin resistance. For more details on this specific study, check out our blog.
Spermidine vs. GLP-1 receptor agonists: a safer, cheaper, more sustainable approach to weight management
GLP-1 receptor agonists have become the go-to treatment for weight loss. These drugs mimic the natural GLP-1 (Glucagon-Like Peptide-1) hormone, which is naturally produced in the intestines and plays a crucial role in regulating blood sugar, appetite, and digestion. GLP-1 helps lower blood sugar by stimulating insulin release and reducing glucagon, a hormone that raises blood sugar. It helps slow digestion by delaying gastric emptying, which helps you feel full for longer, and reduces appetite by acting on the brain to promote feelings of satiety. Medications like Ozempic are GLP-1 receptor agonists, meaning they mimic GLP-1 in the body but last much longer. However, they also come with potential moderate to severe side effects, such as nausea, pancreatitis, and muscle loss.
In contrast, spermidine works through a multi-faceted approach to support your metabolism, with no negative side effects (provided you get it from a healthy diet or a natural high-quality supplement). While GLP-1 agonists can provide rapid weight loss primarily by reducing appetite, spermidine offers a more holistic approach by improving metabolic flexibility, reducing inflammation, restoring gut health, and supporting mitochondrial function. In addition to these benefits, spermidine also offers broader advantages, including cardioprotection, neuroprotection, and promoting longevity. Last but not least, supplementing with spermidine is also far more affordable compared to the high cost of GLP-1 receptor agonists.
Given its wide range of benefits, spermidine represents a compelling option for those seeking natural and sustainable weight management solutions.
Comparison of natural spermidine supplements and GLP-1 receptor agonists (e.g., Ozempic) for metabolic health and weight management. © 2025 Melissa Cano. All rights reserved.
