by Yekta Dowlati, PhD

According to the World Health Organization (WHO), approximately 2 billion adults globally are overweight, with 650 million classified as obese. Projections suggest that, if current trends persist, the number of overweight adults could reach 2.7 billion by 2025, with the obese population surpassing 1 billion.^1,2 Obesity, a complex condition, emerges from an interplay of genetic, societal, and environmental factors and induces metabolic alterations, including changes in gut microbiota, systemic inflammation, and intestinal barrier dysfunction.^3,4 Approximately 31% of obese individuals exhibit metabolic syndrome, characterized by a constellation of symptoms including abdominal obesity, dyslipidemia, hyperglycemia, and hypertension, thereby amplifying the risk of cardiovascular and cerebrovascular diseases.⁵ Additionally, it is implicated in the development of type 2 diabetes mellitus, various chronic inflammatory disorders such as non-alcoholic fatty liver disease, rheumatoid arthritis, certain cancers, and exacerbates mental health issues, including anxiety and depression.⁶ Obesity assessment typically relies on the Body Mass Index (BMI), with an ideal range of 18.5–24.9.⁷ Despite extensive research, current pharmacological interventions for obesity are limited by their toxicity and unintended side effects,⁸ leading to a heightened interest in herbal medicine and plant-based treatments for obesity management.

The burgeoning field of nutritional science increasingly recognizes the pivotal role of phytonutrients in sustaining health and preventing diseases. For healthcare professionals, understanding the molecular mechanisms and physiological effects of these compounds and their synergistic interactions is essential. A diet centered around plant-based foods such as fruits, vegetables, and fiber-rich cereals provides essential phytonutrients, including vitamins, carotenoids, polyphenols, and minerals. Phytonutrients, also known as phytochemicals, are plant-derived nutrients that have been at the forefront of recent research due to their potential impact on metabolic health and weight management.^9,10 Consuming phytonutrients is a safe, widely accessible, and cost-effective method to manage obesity and diabetes, primarily by modulating fundamental physiological processes involved in appetite, metabolism, and insulin sensitivity. ^11-13 Phytonutrients combat obesity through five key mechanisms: acting as lipase inhibitors, suppressing appetite, regulating thermogenic energy expenditure, controlling adipocyte differentiation, and managing lipid metabolism.¹⁴ Among these phytonutrients, berberine, cinnamon, fenugreek, inositol, and certain probiotics are notable for their clinical evaluation for weight management effects, which we will delve further into.

Berberine

Derived from traditional Chinese medicinal herbs, berberine is an isoquinoline alkaloid known for its metabolic benefits, primarily through its action on various molecular targets and pathways.¹⁶ Its primary mode of action in weight management involves activating the AMP-activated protein kinase (AMPK) pathway, crucial for regulating energy homeostasis.¹⁷ Activation of AMPK by berberine leads to improved insulin sensitivity, increased cellular glucose uptake, and decreased gluconeogenesis in the liver.¹⁸ Additionally, it elevates AMPK-dependent triglyceride lipase in adipose tissue, promoting sustained weight loss and preventing obesity.¹⁹

Another mechanism involves the modulation of gut microbiota, increasing the abundance of beneficial bacteria like Akkermansia muciniphila and Bifidobacteria, which are known for their anti-obesity and anti-inflammatory properties and inhibiting the growth of pathogenic strains.²⁰ It also strengthens the gut barrier, preventing the translocation of pro-inflammatory bacterial components like lipopolysaccharides (LPS) into systemic circulation, which is linked with obesity and insulin resistance.²¹ Berberine also enhances the activity of the liver’s low-density lipoprotein receptor (LDLR) gene by stabilizing its messenger RNA, resulting in more efficient removal of LDL-cholesterol.²² Studies have also demonstrated that berberine boosts insulin release from islet cells by increasing glucagon-like peptide-1 (GLP-1) levels. Inhibition of glycosidase can diminish the movement of glucose across the intestinal epithelium, contributing to its antihyperglycemic impact.²³ A meta-analysis of 12 studies revealed that berberine treatment significantly reduced body weight and BMI (p<0.001) and diminished waist circumference (p=0.018).²⁴

Cinnamon

Cinnamon, sourced from the inner bark of trees in the Cinnamomum genus of the Lauraceae family, is prevalent in regions such as South America, Australia, and Asia.²⁵ Its constituents have anti-inflammatory, antioxidant, anti-tussive, anti-arthritic, antimicrobial, and antifungal effects, making cinnamon a multifaceted natural remedy.²⁵ Known for its high content of polyphenolic compounds such as cinnamaldehyde, cinnamon is recognized for its insulin-mimetic properties that enhance insulin sensitivity and reduce fasting blood glucose levels.²⁶  This spice not only improves glucose uptake in peripheral tissues but also stimulates thermogenesis and fat oxidation through the activation of metabolic pathways involving uncoupling protein-1 (UCP1) in adipose tissue.²⁷ Additionally, cinnamon alters gut microbiota composition, increasing beneficial bacterial strains, improving gut barrier function and reducing systemic inflammation associated with obesity and metabolic syndrome.²⁸ Its anti-inflammatory effects, coupled with the ability to modulate adipokines and appetite-regulating hormones like leptin, visfatin, and ghrelin, underscore cinnamon’s potential in weight management and obesity prevention.²⁵ A 2019 meta-analysis, evaluating 21 eligible studies, showed a significant effect of cinnamon on reducing weight (p=0.002), BMI and waist to hip ratio (p<0.001).²⁹ This effect was observed in studies with the duration of 12 weeks or more.  Despite these promising results, inconsistencies in research findings necessitate more in-depth studies to fully understand cinnamon’s role in dietary interventions targeting obesity and metabolic syndrome.

Fenugreek

Commonly utilized in traditional medicine, Trigonella foenum-graecum Linn, better known as fenugreek, is acclaimed for its effectiveness in weight management and metabolic health improvement and has been investigated for a range of health benefits.³⁰ Studies have found that fenugreek has antimicrobial, cholesterol-lowering, anti-inflammatory, hypoglycemic/antidiabetic, and antitumor potential.³¹  The primary active compound galactomannan, a water soluble dietary fiber, contributes to a sensation of satiety by delaying gastric emptying, resulting in reduced caloric intake. Fenugreek also contains saponins, which interact with bile acids to reduce cholesterol levels, influencing lipid metabolism.³² This cholesterol-lowering effect is supported by a meta-analysis of clinical studies, demonstrating fenugreek’s significant impact on lipid profiles in hypercholesterolemic and type 2 diabetic individuals.³³ Fenugreek’s impact on pancreatic lipase also diminishes fat absorption, aiding in weight regulation. Additionally, the amino acid 4-hydroxyisoleucine in fenugreek enhances insulin sensitivity, facilitating more efficient glucose uptake by cells, particularly in insulin-resistant individuals.³⁴ A double-blind randomized placebo-controlled study spanning 14 days with 12 healthy male participants revealed that intake of 1.2 grams of fenugreek seed extract daily resulted in an approximate 12% reduction in their overall calorie intake and a 17% decrease in their daily fat consumption.³⁰ Another single blind, randomized, crossover investigation of 18 people with obesity established that 8 grams of fenugreek fiber with breakfast significantly increased satiety and reduced energy intake in next meal.³⁵

Moreover, fenugreek has shown potential in enhancing the secretion of the incretin hormone GLP-1, crucial for glucose homeostasis and appetite regulation. GLP-1 enhances insulin secretion in a glucose-dependent manner, improving postprandial glucose control and promoting satiety, leading to reduced food intake.³⁶ The polyphenolic compounds in fenugreek exert antioxidant effects, mitigating oxidative stress associated with obesity and metabolic disorders. The synergistic action of these compounds – galactomannan, saponins, 4-hydroxyisoleucine, and polyphenols – in fenugreek, contributes to its potential as a natural aid in weight management.

Inositol

Inositol, a naturally occurring sugar alcohol found in foods like fruits, vegetables, beans, grains, and nuts, are beneficial in treating conditions like polycystic ovary syndrome (PCOS), metabolic syndrome, and gestational diabetes.³⁷ Supplementation with inositol, notably in myo-inositol (MI) and di-chiro inositol (DCI) forms, significantly impacts weight regulation via its insulin-mimetic activity that modulates insulin signal transduction.^37,38 This action augments insulin sensitivity, thereby modulating post-prandial glucose fluctuations and enhancing glycemic control. Consequently, this leads to a reduction in caloric overconsumption driven by appetite dysregulation.³⁸ The action of inositol phosphoglycan (IPG), containing MI or DCI, as a secondary messenger in insulin signaling, is pivotal. IPG activates enzymes for glucose uptake and use. Notably, variations in IPG levels, often seen in individuals with diabetes or obesity, underscore its critical function in metabolic regulation.³⁷

Furthermore, inositol may improve lipid profiles by enhancing lipid metabolism and reducing insulin resistance, potentially through the modulation of lipase activity and lipid absorption, adds another layer to its weight management capabilities. This involves decreasing visceral fat weight, hepatic lipid accumulation, and insulin secretion, while increasing adiponectin concentrations, collectively contributing to favorable lipid profile changes.³⁹ A recent meta-analysis on 15 controlled clinical trials by Zarezadeh et al., found that inositol supplementation has strong positive effect on BMI reduction (p<0.001).³⁷ This was achieved at doses under 1 g/d over 3 months. In a 16-week, double-blind, placebo-controlled trial involving 283 PCOS patients, those receiving 200 mg/d of inositol experienced a significant weight loss and leptin reduction compared to the placebo group (p<0.05).⁴⁰ In another study, obese PCOS patients undergoing an 8-week treatment with 2g/d of myo-inositol demonstrated a notable reduction in BMI.⁴¹ The dual action of inositol in modulating glucose metabolism and lipid profiles, along with its impact on hormonal balance, makes it a promising agent for obesity treatment and overall metabolic health improvement.

Bifidobacterium lactis 420

Bifidobacterium animalis ssp. lactis 420 (B420) has garnered scientific attention for its role in weight loss and obesity management. This probiotic strain, plays a pivotal role in weight management by modulating the gut microbiome, enhancing intestinal barrier function, improving insulin sensitivity, reducing metabolic endotoxemia and tissue inflammation.^42,43 It’s shown to positively affect lipid metabolism and energy homeostasis, possibly via short-chain fatty acid (SCFA) production. By modulating the microbiome, particularly increasing beneficial bacteria like A. muciniphila, B420 demonstrates a novel approach to managing weight and improving overall metabolic profiles. Individuals with obesity, type 2 diabetes, and related conditions often exhibit lower levels of A. muciniphila. Conversely, a higher presence of this bacterium correlates with improved metabolic markers, such as balanced glucose levels, triglyceride management, and favorable body fat distribution. In a randomized double-blind placebo-controlled study by Stenmann and colleagues, 225 overweight healthy adults were assigned to four groups: placebo, polydextrose fiber, B420, and a combination of polydextrose fiber and B420 for six months without dietary or caloric changes. B420 groups showed a significant decrease in body fat mass by 4.0%, waist circumference by 2.4%, and daily energy intake by approximately 300 kcal.⁴⁴

The global increase in obesity is driving the exploration of phytonutrients as anti-obesity agents due to their health-promoting properties. Current research focuses on understanding their molecular mechanisms and harnessing underutilized plant sources for these nutrients. The creation of functional foods and supplements enriched with these phytonutrients presents a promising strategy to bolster public health and address obesity. 

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Yekta Dowlati, PhD, serves as the Medical Education Manager at Metagenics. Dr. Dowlati earned her PhD in Medical Sciences from the University of Toronto, along with her MSc in Pharmacology. Her academic credentials also include a BSc in nutrition. She furthered her expertise with a postdoctoral fellowship in Neuropsychopharmacology at the Centre for Addiction and Mental Health in Toronto. Dr. Dowlati’s research portfolio includes multiple clinical trials, and she has contributed to the scientific community through her authorship and co-authorship of articles in prestigious journals, alongside presenting her work at numerous national and international conferences. Before her tenure at Metagenics, she excelled as a senior medical writer and led medical writing teams, demonstrating her passion for learning and education to improve public health. Beyond her professional commitments, Dr. Dowlati cherishes family time, indulging in travel, fitness, and cooking, which speaks to her balanced approach to life.