Obesity is typically defined using body mass index (BMI), which is a ratio of weight to height. A BMI of 30 or higher meets the clinical threshold for obesity. While BMI is useful for population-level screening, it does not distinguish between fat and muscle or indicate where fat is distributed. For that reason, clinicians often consider waist circumference or body composition measurements, which provide a clearer picture of metabolic risk.

Over the past half-century, obesity rates have risen dramatically worldwide⁽¹⁾.

The condition often begins early in life and frequently persists into adulthood. Although excess calorie intake and low physical activity are important contributors, they are only part of the story. Body weight is tightly regulated by interconnected biological systems that influence hunger, metabolism, fat storage, and energy expenditure.

One of the most influential of these systems is the endocannabinoid system (ECS).

The Endocannabinoid System Is A Central Regulator of Energy Balance

The ECS is a cell-signaling network that helps maintain physiological balance. It was identified in the 1990s after researchers investigated how Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, acts in the body⁽²⁾. 

That work led to the discovery of specific proteins on cell surfaces that respond to chemical signals,  now known as cannabinoid receptors.

Two primary receptors are involved:

• CB1 receptors: Found predominantly in the brain but also present in peripheral tissues such as fat, liver, muscle, and the gut
• CB2 receptors: Located mainly in immune cells and involved in inflammation
  The body produces its own cannabinoid-like molecules, including anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These compounds bind to CB1 and CB2 receptors and help regulate appetite, reward processing, inflammation, glucose metabolism, and fat storage^(2,3).

Under healthy conditions, the ECS acts as a fine-tuning system. It helps ensure that energy intake and energy expenditure remain in balance. In obesity, however, this system often becomes chronically overactive, particularly through CB1 signaling, shifting the body toward increased food intake and greater energy storage⁽³⁾.

How the ECS Contributes to Weight Gain

In the Brain: Appetite and Food Reward

CB1 receptors are abundant in brain regions that regulate hunger and reward, including the hypothalamus and limbic system. When activated, they increase appetite and amplify the pleasurable aspects of eating⁽⁴⁾. 

Foods high in fat and sugar appear to stimulate this system particularly strongly.

This effect is not simply about taste preference. CB1 activation heightens the motivational drive to seek food, especially calorie-dense food. The result can be persistent hunger signals even when energy needs are met.

Leptin, a hormone released by fat tissue, normally suppresses appetite and dampens ECS activity. In many individuals with obesity, leptin resistance develops, meaning the brain no longer responds effectively to leptin’s signals. When that regulatory brake weakens, CB1-driven appetite signaling can become more pronounced⁽⁴⁾.

Figure: Schematic illustration of the endocannabinoid system role in the regulation of metabolic processes. CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; CNR1, endocannabinoid type 1 receptor gene; CNR2, endocannabinoid type 2 receptor gene; FAAH, fatty acid amide hydrolase; NAPE-PLD, N-acyl phosphatidylethanolamine phospholipase D. (Adapted from Schulz et al., 2021)

In Adipose (Fat) Tissue: Promoting Fat Storage

The ECS also acts directly on fat cells, and activation of CB1 receptors in adipose tissue:

• Stimulates the formation of new fat cells
• Increases the storage of triglycerides within those cells
• Reduces fat breakdown
• Lowers adiponectin, a hormone that enhances insulin sensitivity

Adiponectin plays a protective metabolic role by improving the body’s response to insulin and supporting fat oxidation. When adiponectin levels fall, insulin resistance becomes more likely.

In this way, an overactive ECS does more than increase calorie intake, it alters how calories are processed and stored, favoring accumulation rather than utilization^(3,5).

In Brown Fat: Reducing Energy Expenditure

Brown adipose tissue burns calories to generate heat through thermogenesis, contributing to overall energy expenditure. CB1 activation suppresses thermogenesis in brown fat, reducing calorie burning⁽⁵⁾. 

Even modest reductions in energy expenditure can contribute to gradual weight gain over time.

In the Liver and Skeletal Muscle: Impairing Metabolic Control

In the liver, CB1 signaling stimulates fat synthesis and accumulation, contributing to nonalcoholic fatty liver disease and worsening insulin resistance⁽⁶⁾.

The liver becomes more likely to convert excess carbohydrates into fat and less responsive to insulin’s regulatory effects.

In skeletal muscle, CB1 activation reduces glucose uptake and decreases fat oxidation. When muscles use less glucose and burn less fat, blood sugar levels rise more easily, further straining metabolic control^(3,6). 

Together, these changes help explain why obesity often coexists with type 2 diabetes and other features of metabolic syndrome.

In the Gut: Influencing Hunger and Absorption

The ECS is also active in the gastrointestinal tract. It affects gut motility, nutrient absorption, and satiety signaling. Levels of endocannabinoids in the intestine increase during fasting, intensifying hunger, while high-fat diets can elevate intestinal endocannabinoid levels⁽⁷⁾. 

This interaction may reinforce dietary patterns that promote weight gain.

The Gut Microbiome and Inflammation

The gut microbiome is the community of microorganisms living in the intestines, and it interacts closely with the ECS. When microbial balance is disrupted, a state known as dysbiosis, low-grade inflammation can increase and the intestinal barrier may become more permeable.

This permeability allows bacterial components such as lipopolysaccharides (LPS), which are molecules found in the outer membrane of certain bacteria to enter circulation. Elevated LPS levels can stimulate CB1 signaling and promote inflammation in fat tissue^(7,8). 

The result is a bidirectional relationship: changes in the microbiome can amplify ECS activity, and heightened ECS signaling can worsen metabolic inflammation.

Genetic Influences

Genetic variation also plays a role. Differences in genes such as CNR1 (which encodes the CB1 receptor) and FAAH (which encodes an enzyme that breaks down endocannabinoids) can influence baseline ECS activity. Some variants are associated with higher endocannabinoid levels, increased appetite, abdominal fat accumulation, and insulin resistance⁽³⁾.

These genetic effects do not determine destiny, but they can alter susceptibility, especially when combined with environmental factors.

Therapeutic Lessons: Blocking CB1

The central role of CB1 in metabolism prompted the development of rimonabant, a CB1 receptor antagonist. Clinical trials demonstrated weight loss and improvements in cardiometabolic risk factors⁽⁹⁾.

However, because CB1 receptors are widely distributed in the brain and influence mood regulation, central blockade led to significant psychiatric adverse effects, including depression and anxiety. The drug was ultimately withdrawn⁽⁹⁾.

Current research is focused on compounds that selectively block CB1 receptors in peripheral tissues such as fat and liver without crossing the blood-brain barrier. The aim is to preserve metabolic benefits while minimizing neurological risk.

A Survival System in a Changed Environment

The endocannabinoid system evolved in a context of food scarcity. A biological network that encourages eating, conserves energy, and promotes fat storage would have enhanced survival during famine. In today’s environment of constant food availability, particularly calorie-dense foods, the same system can contribute to chronic weight gain.

Obesity reflects a complex interplay among neural circuits, hormones, metabolic pathways, the microbiome, genetics, and environmental exposure. The ECS sits at a critical intersection of these systems. Understanding how it functions and how it becomes dysregulated helps explain why appetite can feel persistent, why weight regain is common after dieting, and why obesity is closely linked to metabolic disease.

In today's world of nutritionally deficient food-like products it can be easy to overeat, so if you're looking for a helpful ally in your fight against obesity, SHREDDED-AF can help, especially when it comes to food cravings.

SHREDDED-AF is an advanced multistage thermogenic that focuses on boosting metabolism, suppressing cravings, and providing all-day energy and mental clarity without the crash!

References:

Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: A systematic analysis. Lancet. 2014;384:766-781.

Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946-1949.

Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8:585-589.

Cota D, Marsicano G, Tschöp M, et al. The endogenous cannabinoid system affects energy balance via central mechanisms. J Clin Invest. 2003;112:423-431.

Pagotto U, Marsicano G, Cota D, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73-100.

Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298-1305.

Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Nat Commun. 2010;1:1-11.

Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761-1772.

Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients. Lancet. 2005;365:1389-1397.