Tsaban G, Yaskolka Meir A, Zelicha H, et al. Diet-induced fasting ghrelin elevation reflects the recovery of insulin sensitivity and visceral adiposity regression. J Clin Endocrinol Metab. 2022;107(2):336-345.
To examine changes in fasting ghrelin levels (FGL) during weight loss and to document metabolic changes related to FGL after weight loss
Unblinded, randomized clinical trial with 3 dietary intervention arms
There were 294 subjects in this trial, with 88% men (women=35; men=259).
Inclusion criteria: All participants were over 30 years of age and had abdominal obesity (waist circumference [WC] >102 cm for men; >88 cm for women) or dyslipidemia (HDL [high-density lipoproteins] cholesterol levels <40 mg/dL for men; <50 mg/dL for women), or both.
At baseline, 52% of participants were normo-glycemic, 37% were prediabetic, and 11% had type 2 diabetes (HbA1c 5.2+0.31%, 5.5+0.34%, and 6.8+1.0%, respectively).
Triglyceride levels were greater than 150 for all participants.
Several exclusion criteria were used, including:
- Inability to be physically active
- Serum creatinine > 2mg/dL
- Abnormal liver function
- Any illness that may require hospitalization
- Active cancer or chemotherapy in the last 3 years
- Treatment with warfarin
- Any implant that precludes the use of magnetic resonance imaging (MRI)
All participants were randomized into 1 of 3 treatment arms:
- Healthy Dietary Guidelines (HDG). The people in the HDG group were instructed to exercise and were counseled on “basic health-promoting guidelines for achieving a healthy diet.”
- Mediterranean Diet (MED). The MED group followed a calorie-restricted diet, low in simple sugars, and ate chicken and fish in place of beef and lamb.
- Green Mediterranean Diet (green-MED). The green-MED group was similar to the MED group, but it also included 3 to 4 cups per day of green tea and 100 grams of Wolffia globosa (also known as Mankai or duckweed) daily. These items added an additional 800 mg polyphenols to the green-MED diet. The study did not specify the exact type of physical activity that was recommended.
All the treatment arms also included physical activity (PA). The MED groups (2 and 3) both supplemented with 28 grams of walnuts per day (160 kcal, 84% fat, mostly omega-3, linolenic acid, and 440 mg polyphenols/day, mostly ellagic acid [hydroxybenzoic acids]), free of charge.
Study Parameters Assessed
The investigators assessed the following study parameters:
- Fasting ghrelin levels
- Abdominal adiposity (visceral adipose tissue [VAT])
- Intrahepatic fat
- Blood pressure
- Weight loss
- Homeostatic model of insulin resistance (HOMA)
- Adipose tissue stores were assessed by MRI
Primary Outcome Measures
The primary outcome measures were fasting ghrelin levels and adipose tissue deposits at baseline and at 18 months.
Lower fasting ghrelin levels correlated with higher levels of the following cardiovascular risk measures: blood pressure, visceral adipose tissue, hepatic fat stores, and leptin (P<0.05).
After 18 months there was a similar amount of weight loss noted among the 2 MED groups. The increase in FGL was highest in the green-MED group (10.5%) compared to the HDG and MED group respectively (1.3% and 5.4%). There was a statistically significant increase in FGL between the green-MED and HDG groups (P=0.03).
Women had greater baseline FGL versus men (719±257 pg/mL vs 480±188 pg/mL, P<0.001).
The change in fasting ghrelin levels differed significantly between men and women at the 18-month mark (+7.3±26.6% vs –9.2%±21.3% respectively with P=0.001).
Further analysis revealed that, in men, FGL at 18 months correlated with decreased VAT and improved insulin resistance. This held true even after adjusting for weight loss (HbA1c: r=–0.216; HOMA: r=–0.154; HDL-c: r=0.147; VAT: r=–0.221; P<0.05 for each of these measures).
The results differed for women. The female participants saw a nonsignificant increase in FGL after 6 months but a decrease in FGL at the 8-month mark. The reduction in FGL was greater in the green-MED group compared to the MED and the HDG groups (HDG: –2.8 +5.5%; MED: –5.8 + 7.3%; green-MED: –20.1 + 7.1%; P=0.259). In other words, there was statistically significant interaction found between sex and the green-MED diet regarding the effect on FGL (P=0.022.) The authors speculated that this may be due to a sex-specific effect of the diet, but there were so few women in this study that the idea necessitates further study.
In clinical practice I have noted that some of my patients who are obese do not display insulin resistance. On the other hand, some patients have less overall body adiposity but clearly display insulin resistance. In many cases the latter have been those who have localized abdominal obesity rather than a whole-body distribution of adipose tissue. From clinical observation, it seems to me that whole-body adiposity does not always track with insulin resistance.
Indeed abdominal obesity, which is sometimes called “visceral obesity,” is strongly linked with the metabolic changes seen in insulin resistance. A few of the many metabolic aberrations correlated with visceral obesity include small dense low-density lipoprotein (LDL) particles, increased production of triglycerides, increased production of inflammatory cytokines in adipose tissue, and increased production of very low density lipoprotein (VLDL) particles in the liver.2
Patients often state that they do not have much adipose tissue apart from their “belly fat” and then ask me, “What can I do to lose this fat around my belly?” Unfortunately, I can’t say that I’ve ever had a good answer to this question. Perhaps based on the current study I can answer, “Exercise and eat a Mediterranean-style diet high in polyphenols because this has been shown (at least in men) to lower visceral obesity, raise ghrelin levels, and lower insulin resistance.”
As often happens in science and medicine, we adopt a model that does not fit all individuals. Perhaps we see a correlation between factors that can easily be measured and we assume causation. The hypothesis of cardiovascular events and total cholesterol, HDL, and LDL may be an example of this phenomena. There is likely some degree of individual biochemistry at play, so it does not hold true for everyone. We all know people who had high total cholesterol levels, low HDL, and high LDL and lived a long, healthy life.
A combination of cholesterol particle sizes, markers of inflammation, amino acid metabolism, and oxidative stress may give a much more complete picture of cardiovascular risk. Panels that measure these markers are now more easily accessible through mainstream labs. I have found these panels to be much more useful for directing natural therapeutics than the classic total cholesterol, HDL, and LDL panel, which does not give us enough granular data but has been used for decades nonetheless.
Perhaps the situation with whole-body adiposity and insulin resistance will turn out to be a similar oversimplification. The current study offers clues in this direction.
Is insulin resistance caused by overall body adiposity or is overall body adiposity just a red herring that we are following? Perhaps the picture is more nuanced and involves a relationship between visceral obesity and ghrelin? If this is the case, what can we do clinically to alter neurohormones like gherlin?
One thing is certain from this study: The positive effect of the diet and exercise interventions on VAT and insulin resistance was not only about “being overweight.” The relationship between fasting ghrelin levels, improved VAT, and decreased insulin resistance held true even when researchers controlled for the variable of weight loss. With this in mind, the current authors state: “Thus, it is plausible that dietary interventions aiming to increase FGL, and not necessarily weight per se, might yield cardiometabolic benefit in patients with metabolic syndrome.”
The term “ghrelin” was coined in 1999 when this gastric peptide was shown to bind to a receptor in the pituitary and help regulate the release of growth hormone.3 Ghrelin is a type of peptide that we now call a “neurohormone,” and lately these peptides have been getting a lot of airtime.
Some of the more recently developed diabetes drugs take advantage of the neurohormones involved in the “gut-brain axis.” Glucagon-like peptide-1 receptor agonists (GLP-1 RA) medications are an example. GLP-1 is an incretin hormone secreted from the L cells of the ilium and colon in response to the ingestion of food. L cells are a type of “enteroendocrine cell” that form part of the gut-brain axis. GLP-1 increases pancreatic beta cell insulin secretion, slows gastric emptying, and increases satiation. All of these mechanisms assist with blood sugar regulation.4 Interestingly, the current authors mention a connection between ghrelin and GLP-1 secretion. Perhaps this is 1 of the interconnecting ways that ghrelin exerts its positive effect on body composition and insulin sensitivity in this study.
Ghrelin is a type of peptide that we now call a 'neurohormone,' and lately these peptides have been getting a lot of airtime"
Whenever we get too reductionistic in our thinking, holism comes knocking on our door once again. The current study is an example of that. Exercise, dietary habits, adiposity, fasting ghrelin, and the gut-brain axis are all related in an intricate holistic web. You can never get away from healthy lifestyle and dietary habits even though they may not be as exciting to talk about as drugs and supplements. Diet and lifestyle modifications remain the most powerful of medicines and the most difficult to “bottle.”
A major challenge in recommending a healthy diet is actually defining what it means. Even a cursory glance at the different dietary styles promoted since the 1970s will make this quite clear. In recent years the Mediterranean diet pattern has attracted a lot of positive attention. Previous research has shown that it lowers various cardiometabolic risk factors.5
One of the cardinal factors of a “healthy diet” that seems to be widely agreed upon is that it should be high in polyphenols.6 This study seems to bear this out. The benefits of green tea polyphenols have been appreciated for a long time. Green tea has innumerable well-researched benefits such as enhancing apoptosis, inhibiting nuclear factor kappa beta, and decreasing angiogenesis, to name only a few.7
The observation that adding green tea and Wolffia globosa into the green-MED group enhanced the diet’s effects is fascinating to me. The authors hypothesized that this effect may be due to the higher polyphenol and fiber content of the green-MED diet. Indeed a 2017 study showed that total acetylated ghrelin levels were increased the next day after consumption of carob fiber pulp, which is high in both fiber and polyphenols.8
Wolffia globosa may turn out to be useful for diabetics. It has been shown to promote lower postprandial glucose excursions when used as a dinner replacement shake compared to an isocaloric yogurt-based shake.9 It is a common observation in clinical practice that fasting blood sugars are often stubbornly high in diabetics due to the “dawn phenomenon.” Wolffia globosa may prove to be useful for tackling this issue. As an extra bonus, Wolffia globosa is a sustainable source of plant-based protein and absorbable bio-active vitamin B12.8,9