Ghrelin Paradox: Unlocking New Avenues in Obesity Management

Ghrelin Paradox: Unlocking New Avenues in Obesity Management
Dimpi Desai, MD; Ashni Dharia, MD DISCLOSURES | June 21, 2024

Despite their best efforts, 80% of people who lose weight regain itand many end up heavier within 5 years. Why? Our bodies fight back, revving up hunger while slowing metabolism after weight loss. In ongoing obesity discussions, ghrelin is in the spotlight as the “hunger hormone” playing a crucial role in driving appetite and facilitating weight gain.

Weight loss interventions, such as diet or gastric bypass surgery, may trigger an increase in ghrelin levels, potentially fueling long-term weight gain. Consequently, ghrelin remains a focal point of research into innovative antiobesity treatments.

Ghrelin, a hormone produced in the stomach, is often called the “hunger hormone.” Ghrelin is a circulating orexigenic gut hormone with growth hormone–releasing activity. In the intricate balance of energy, central and peripheral peptides such as ghrelin, leptin, adiponectin, and insulin play crucial roles. They regulate hunger, fullness, and metabolic rates, shaping our body weight outcomes.

Since the discovery of ghrelin, in 1999, research in mice and people has focused on its effect on regulating appetite and implications for long-term weight control. When hunger strikes, ghrelin levels surge, sending signals to the brain that ramp up the appetite. Following a meal, ghrelin decreases, indicating fullness.

Studies have found that people who were injected with subcutaneous ghrelin experienced a 46% increase in hunger and ate 28% more at their next meal than those who didn’t receive a ghrelin injection.

We might expect high levels of ghrelin in individuals with obesity, but this is not the case. In fact, ghrelin levels are typically lower in individuals with obesity than in leaner individuals. This finding might seem to contradict the idea that obesity is due to high levels of the hunger hormone.

Excess weight could increase sensitivity to ghrelin, where more receptors lead to higher hunger stimulation with less ghrelin. Beyond hunger, ghrelin can also lead us to eat for comfort, as when stressed or anxious. Ghrelin and synthetic ghrelin mimetics increase body weight and fat mass by activating receptors in the arcuate nucleus of the hypothalamus (Müller et al; Bany Bakar et al). There, it also activates the brain’s reward pathways, making us crave food even when we are not hungry. This connection between ghrelin and emotional eating can contribute to stress-induced obesity.

In my clinical practice, I have seen individuals gain maximum weight when they are under more stress and are sleep-deprived. This is because ghrelin levels increased in these scenarios. This elevation of ghrelin in high-stress, low-sleep situations affects weight gain in women during the postpartum period and menopause.

Evidence also suggests that certain foods affect ghrelin levels. After a person eats carbohydrates, their ghrelin levels initially decrease quickly, but this is followed by a rise in ghrelin, leading them to become hungry again. In contrast, protein intake helps suppress ghrelin levels for longer. Hence, we advise patients to increase protein intake while reducing their carb intake, or to always eat protein along with carbs.

It makes sense that when individuals with obesity lose weight by fasting or caloric restriction and try to maintain that weight loss, their bodies tend to produce more ghrelin. This effect might explain why people who lose weight often find it hard to keep it off: Rising ghrelin levels after weight loss might drive them to eat more and regain weight.

Two prominent weight loss surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), have opposite effects on ghrelin levels, reflecting their distinct mechanisms for weight loss. SG involves removal of the gastric fundus, where ghrelin is produced, resulting in a significant decrease in ghrelin levels; RYGB operates through malabsorption without directly affecting ghrelin production. Despite these differing approaches, both techniques demonstrate remarkable weight loss efficacy. Research comparing the two procedures reveals that SG leads to decreased fasting plasma ghrelin levels, whereas RYGB prompts an increase, highlighting the additional appetite-reducing mechanism of SG through ghrelin suppression. This contrast underscores the intricate role of ghrelin in appetite regulation and suggests that its manipulation can significantly influence weight loss outcomes.

With the effect of ghrelin in stimulating appetite being established, other studies have explored the relationship between ghrelin and insulin resistance. A meta-analysis by researchers at Qingdao University found that circulating ghrelin levels were negatively correlated with insulin resistance in individuals with obesity and normal fasting glucose levels. The findings suggest that the role of ghrelin in obesity might extend beyond appetite regulation to influence metabolic pathways and that ghrelin may be a marker for predicting obesity.

Researchers are exploring potential therapeutic targets focusing on ghrelin modulation. Although selective neutralization of ghrelin has not yielded consistent results in rodent models, the interplay between ghrelin and LEAP2— a hormone that attaches to the same brain receptors — could be an area of interest for future obesity treatments.

Could ghrelin be the key to tackling obesity? Blocking ghrelin pharmacologically might be a strategy to keep weight off after weight loss, and it could help prevent the typical rebound effect seen with diets and withdrawal of medications. Considering the high rates of weight regain after diet-induced weight loss and withdrawal of weight loss medications, targeting ghrelin might be the missing link in long-term obesity treatment. It could be a valuable approach to improving long-term outcomes for obesity. However, these blockers might have significant side effects, given that ghrelin affects not only hunger but also the brain’s reward and pleasure centers. Therefore, caution will be needed in developing such medications owing to their potential impact on mood and mental health.

With ghrelin playing roles in hunger, reward pathways, and energy regulation, understanding this hormone is crucial in the fight against obesity. Stay tuned for future research that could shed light on the underlying mechanisms at play and hopefully results in clinical action steps.