In overweight and obese people, the goal of treatment is not just to reduce weight, but to promote better body composition, with a reduction in overall body fat while preserving muscle mass, in order to reduce associated morbidities and mortality. In addressing body fat reduction, it's important to focus on the role of visceral adipose tissue (VAT) — more so than subcutaneous adipose tissue (SAT) — because of VAT's effects on a wide range of metabolic and cardiovascular conditions. Indeed, fat distribution is a better predictor of such diseases than overall weight.1,2
Visceral Adipose Tissue
In people living with obesity, fat stores can make up to 60% of their total body weight, of which the majority (>80%) is stored as SAT and the rest as VAT.3 VAT is the fat that is stored around internal organs. It is distinct from ectopic fat, which describes triglycerides stored within non-adipose tissue that normally contains only small amounts of fat.2 Some fat depots can be classified as both visceral (surrounding an organ) and ectopic (within an organ). Both VAT and ectopic fat depots exhibit dysfunctional metabolic activity with distinct biological characteristics, resulting in a wide range of pathologies.1
Morphology and Metabolic Effects of VAT
Adipose tissue is no longer seen as passive tissue that merely provides cushioning to bodily structures. Rather, it is highly metabolically active, with differences in white and brown fat, and in its location. Healthy VAT has various roles, including structural, metabolic, and thermogenic support of organs, immunogenic regulation, and endocrine functions.2 Adipose tissue produces more than 600 different adipokines, including hormones, cytokines, and growth factors, some of which have either pro- or anti-inflammatory effects (e.g., leptin and adiponectin, respectively, to name two).4 Dysfunctional secretion of adipokines is thought to link obesity and associated diseases.4
SAT is limited in its ability to expand. With positive energy balance, excess fat above SAT's limitation is stored in VAT, whose cells hypertrophy in response.2 It's suggested that this hypertrophy initially occurs without proportional angiogenesis, causing local hypoxia of the VAT, with a subsequent increase in inflammatory cytokines and adipocyte malfunction.2 The enlarged adipocytes are more metabolically active but resistant to insulin's anti-lipolytic effects.1,2 The increase in lipolysis breaks down stored triglycerides and releases free fatty acids (FFAs) which are delivered to ectopic fat depots (e.g., to the liver via the portal vein); FFAs contribute to local and generalized inflammation and to insulin resistance.2
Aging adds to the likelihood of adipocyte dysfunction and excess accumulation of VAT, through hormonal changes, chronic low-grade inflammation, and accumulation of senescent cells.2 Moreover, higher VAT contributes to accelerated aging and has been associated with reduced telomere length, older DNA methylation age, and mitochondrial dysfunction.2
Measuring VAT
The quantity of VAT is thought to be less important than its quality as a predictor of metabolic risk.2 Nevertheless, most studies aim to quantify it. The Body Mass Index (BMI) is accepted as being inadequate, as it doesn't account for lean mass versus fat mass, body fat distribution, or the burden of ectopic and visceral fat depots.3 Clinical methods for measuring VAT include MRI or CT scanning (the most precise), and DEXA scanning. Other approaches include waist circumference, waist-to-hip ratio, and bioimpedance "smart scales". Various indices using anthropometric variables (such as height and waist circumference) have been created, but the visceral adiposity index (VAI) combines both anthropometric and metabolic parameters (waist circumference, with triglyceride, and high-density lipoprotein cholesterol in a (complicated) formulas specific to males and females.4 High VAI scores have been associated with multiple diseases (Box 1).
Consequences of Excess VAT
Multiple animal and human studies have demonstrated a correlation between excess/dysfunctional VAT or ectopic fat (which as noted earlier, occurs as a consequence of dysfunctional VAT) and a wide range of diseases; these are summarized in Table 1.1 In addition, there is an association with mortality, both all-cause and specific (e.g., increased mortality from coronavirus pneumonia).2
Table 1: Effects of excess visceral and ectopic fat depots.1
| Site of Fat | Effects | Associated Conditions |
|---|---|---|
| Mesenteric |
|
|
| Perirenal |
|
|
| Peripancreatic & intrapancreatic |
|
|
| Intrahepatic |
|
|
| Pericardial & epicardial |
|
|
| Intra- and interskeletal muscle |
|
|
CVD=cardiovascular disease; GFR=glomerular filtration rate; MASLD=metabolic dysfunction-associated steatotic liver disease (previously non-alcoholic fatty liver disease); MS=multiple sclerosis; T2DM=type 2 diabetes mellitus.
Interventions to Reduce VAT
Historically, VAT reduction has been addressed by weight loss measures. These comprise lifestyle interventions, surgery, and medications and supplements.
Lifestyle Interventions
Calorie restriction and the Mediterranean diet have been associated with weight loss and a reduction in waist circumference, and intermittent fasting reportedly improves body composition more than unrestricted dieting, all with improvements in cardiometabolic risk factors.3 Physical activity plays an integral role in decreasing cardiometabolic risk factors; in particular, aerobic exercise (at moderate-to-high intensity) decreases VAT, while resistance training does so slightly less effectively and with more variability across studies.2
Although lifestyle interventions are effective, they typically don't target VAT and are difficult to adhere to and maintain.2,3
Surgery
Bariatric surgery has a greater impact on body composition compared to medical therapy, with Roux-en-Y gastric bypass producing more VAT reduction compared to lean mass reduction.2,3 This is associated with improvements in cardiometabolic health, such as remission of type 2 diabetes (T2DM), even after weight regain.2 Gastric banding does not produce the same decrease in VAT, however.2 Mesenteric VAT lipectomy is being investigated as a novel surgical technique utilizing tissue liquefaction.2
Medications
Sodium glucose co-transporter 2 inhibitors have shown a benefit in reducing VAT, SAT and ectopic hepatic fat in patients with T2DM.3 Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have demonstrated they reduce both VAT and SAT in diabetic and non-diabetic patients, alongside improvements in cardiometabolic risk factors.2 However, the drop-off rate in GLP-1 RA use is high due to factors such as side effects, affordability, lack of insurance coverage, and needle phobia.
New strategies being investigated are aimed at some of the metabolic parameters associated with VAT dysfunction, including reducing the senescent cell burden, decreasing leptin, increasing adiponectin, promoting healthy VAT expansion via adipocyte hyperplasia rather than hypertrophy, and inhibiting harmful ceramide and exosome production by adipocytes.2
Other Emerging Strategies
Cold exposure has been suggested as a way to induce browning of VAT, converting white adipocytes into energy burning "beige" or "brown-like" ones and thereby augmenting thermogenesis and reducing VAT. Gene therapy to induce browning has been successfully performed in mice with a subsequent decrease in VAT, improved metabolism and extended lifespan.2 Techniques to alter the gut microbiome (pre- or probiotics or fecal transplants) selectively reduced VAT and inflammation in overweight adults
Very recently, a bioceutical, Amarasate, the active ingredient in Calocurb, has demonstrated a significant reduction in VAT in a weight loss study. Like GLP-1 RAs, Amarasate utilizes the GLP-1 metabolic pathway, but upstream of that hormone's receptors: as a bitter extract of hop flowers, it stimulates bitter taste receptors on enteroendocrine cells lining the length of the gastrointestinal tract, which release three satiety hormones in response, GLP-1, cholecystokinin (CCK), and peptide tyrosine tyrosine (PYY). In an earlier clinical study, GLP-1, CCK, and PYY were increased 6.4-, 6.0-, and 1.7-fold, respectively, with a subsequent 18% reduction in energy intake.5
Amarasate Effectively Reduces VAT
The results of a 24-week double-blind comparison of Amarasate with placebo in overweight or obese people (BMIs 25–35 kg/m2) have recently been published.6 Participants were randomized to receive either Amarasate (500 mg/day in two divided doses taken an hour before the two biggest meals of the day) or placebo. All study members were seen every four weeks for weight and body composition measurements (by multifrequency bioelectrical impedance analysis using an InBody S10 scanner). At those visits they also took part in group seminars at which a dietitian gave general advice about exercise and diet.
Amarasate resulted in a 4.3% weight loss: significantly greater than baseline and placebo.6 This occurred while maintaining muscle mass; in fact, overall fat loss (−4.5 kg) exceeded overall weight loss (−3.8 kg) in the Amarasate group.6 Visceral fat loss was significantly greater in the Amarasate group compared to baseline and to placebo, reducing by 32.5 cm2 (vs. 9.1 cm2 in the placebo group), representing a 3.6 times benefit with the bioceutical (Figure 1).6 As can be seen, the placebo reached a maximum loss of ~−14 cm2 at week 12, after which they began to regain it; in contrast, the fat loss at week 12 in the Amarasate group was −12 cm2 and it continued to decrease through the next 12 weeks.
Amarasate thus provides an effective additional tool to help reduce VAT in overweight and obese individuals in those who are attempting lifestyle interventions to lose weight. It can be used as an alternative to GLP-1 RAs in those unwilling or unable to have these medications, as an exit strategy for patients ceasing their use, or even as an adjunct to them (allowing patients to receive a reduced dose of the GLP-1 RA while maintaining weight loss).
Conclusion
VAT plays a highly important role in the morbidity and mortality that accompanies overweight and obesity. Strategies to effectively reduce VAT include lifestyle interventions, surgery, and medications. An all-natural bioceutical, Amarasate, has recently proven to be another highly effective way to significantly reduce VAT.
