Amarasate stimulates the release of three satiety hormones at once — glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), and peptide tyrosine tyrosine (PYY).1 In addition to the effects of GLP-1 receptor activation, CCK is an additional appetite suppressant that has both central effects on satiety centers and delays gastric emptying, optimizes digestion via bile and pancreatic secretion, and works synergistically with leptin. PYY is linked to a benefit none of the GLP-1 receptor agonists share: preserved, rather than lost, lean muscle mass during weight loss. For prescribers weighing an alternative to GLP-1 RAs, an off-ramp for patients stopping them, or a complementary agent to offset their muscle-loss effects, the mechanism behind this is directly relevant to patient care.
Background
Amarasate is a purified extract of hop flowers, and is the active ingredient in Calocurb® capsules. This supplement activates bitter taste receptors (TAS2Rs) on certain enteroendocrine cells within the gut mucosa, resulting in the release of at least three gut hormones: GLP-1, CKK, and PYY. A clinical study where subjects ingested a 500 mg dose of Amarasate demonstrated increases from baseline of 6.4 times, 6.0 times, and 1.7 times respectively, for GLP-1, CCK, and PYY.1 In that study, the participants went on to eat 18% fewer calories at the subsequent ad libitum meal.
More recently, 24 weeks' use of Amarasate (as two x 125 mg capsules of Calocurb used an hour before the two biggest meals of the day) resulted in a 4.8% weight loss, equivalent to a 5.3% loss when adjusted for muscle-mass gain (p<0.01 for both measures)2. The trial was double-blind, placebo controlled and there were 150 participants; in the placebo arm, there was 0.5% weight loss (and 0.7% muscle-mass adjusted weight loss).
Importantly, in the weight loss study, Amarasate participants preserved their muscle mass. As measured by multi-frequency versions of bioelectric impedance analysis (InBody S10), their mean muscle mass increased by 0.9 kg at week 242. This is in stark contrast to most other weight loss interventions, especially using GLP-1 receptor agonists (RAs), where around 25%–35% of weight loss is due to lean mass reduction.
It has been suggested that the muscle preservation seen with Amarasate is due to the specific hormones it stimulates. This article reviews those and other enteroendocrine hormones to offer an explanation for this distinctive benefit of the nutraceutical.
Enteroendocrine Cells — the Source of Gut Hormones
Enteroendocrine cells (EECs) are distributed throughout the length of the gastrointestinal (GI) tract. They are either open (apical in shape with microvilli) or closed (nearer the basement membrane).3 EECs connect by long projections from their basal surface to vagal afferents, so-called "neuropods".3 Collectively, EECs make up ~1% of the GI epithelium but are the largest endocrine system in humans.3 Following mechanical, neural, or chemical stimulation, EECs release hormones and peptides from secretory microgranules using exocytosis at their basal side. The secreted hormones or peptides directly interact with spinal and vagal afferent neurons via the neuropods or are released into the bloodstream, and can also recruit immune cells.3
In terms of luminal contents, EECs have various receptors for sensing different chemicals including short-chain fatty acids and other microbial metabolites, small peptides, glucose, fructose, bitter tastants and more. Historically, it was believed that specific enteroendocrine cells produce one type of hormone, but more recently, it has been discovered that some produce multiple hormones. These cells have been classified primarily by the predominant hormone they secrete; there are at least 8 subtypes according to this system.3 The cell types differ in the quantity of hormone they produce depending on their location within the GI tract and their maturation , and also in the type of sensory receptors that stimulate production of those hormones.4 Consequently, a system of subclassification has been proposed that includes these variables.4,5 Importantly, changes in gut hormone levels have been demonstrated in obesity and type 2 diabetes mellitus (T2DM).3 The EEC subtypes of particular relevance to appetite, Amarasate, and recently available weight loss medications are summarized in Table 1, along with changes seen in obesity and T2DM.3 They can be grouped into three main categories: ingestion, digestion, and metabolism, as shown in Table 2.5
Amarasate Stimulates Release of Three GI Hormones
As noted above, Amarasate increases the levels of three important GI hormones. As a mostly unabsorbed bitter tastant, it activates TAS2Rs down the length of the GI tract present on L cells and I cells (and also X/A-like cells). As shown in Table 1, this causes the release of GLP-1 and PYY from the L cells, and CCK from the I cells — all of which have effects on CNS satiation/satiety centers and on delaying gastric emptying. In the 24-week weight loss study, Amarasate demonstrated sufficient activation of TAS2Rs with subsequent increases in these three satiation and satiety hormones to induce a mean weight loss of 4.8 kg (vs. 0.4 kg in the placebo group; p<0.01).2 However, Amarasate has further benefits (due to the additional physiological effects of increased CCK and PYY), in addition to satiation and satiety.
GLP-1
The 6.4 times increase in GLP-1 from baseline that Amarasate produces is well over the threshold of 4.0 times that is required to induce a reduction in energy intake.1,7 This impact was supported by the significant weight loss achieved by those in the active arm of the weight loss study.2 GLP-1 release stimulates vagal afferents via neuropods, which then causes release of central GLP-1 that acts as a neurotransmitter within appetite centers within the CNS and also activates signals to delay gastric emptying via stimulation of vagal efferents. It is also noteworthy that Amarasate is barely absorbed; in human pharmacokinetic studies, only 1.4% of hop α and β acids were absorbed.8 Thus, its impact continues throughout the length of the GI tract, including the colon, where TAS2Rs are not stimulated by foods (as macronutrients are largely absorbed within the proximal small intestine).
CCK
As with GLP-1, Amarasate also resulted in a 6 times increase of CCK over baseline.1 Lim et al calculated that the minimum fold change required to reduce ad libitum energy intake is 3.6.7 It is likely that the substantial increase in CCK induced by Amarasate thus contributes to its weight loss effects.
In the GI tract, CCK's effects on ingestion, digestion, and metabolism include:9
- contraction and relaxation of the gallbladder
- regulation of bile acid secretion (aiding fat digestion in the small bowel)
- regulation of gut motility
- inhibition of gastric emptying
- enhancement of leptin secretion
- support of further protein absorption
In the CNS, CCK not only has adirect role in causing fullness via the nucleus tractus solitarius pathways, but also has indirect effects through its synergistic interactions with leptin (which also acts centrally, to induce satiation and increase energy expenditure).9
Moreover, GLP-1 secretion from colonic L-cells is "robustly stimulated" by bile acids;4 increased levels of CCK-induced bile acids may thus further raise GLP-1.
PYY
A 500 mg dose of Amarasate increased baseline PYY levels 1.7-fold.1 While that PYY increase doesn't cross the threshold to reduce energy intake for PYY (3.1-fold), it likely contributed to the weight loss achieved in the 24-week study in combination with the GLP-1 and CCK effects.7 Furthermore, it may have had a role in preserving muscle mass in the weight loss study, by activating PYY receptors that modulate skeletal muscle repair and growth. This would explain why 24 weeks' treatment with Amarasate resulted in a 0.9 kg muscle mass weight gain — in marked contrast to the substantial lean mass loss encountered with GLP-1 RAs and related medications.
PYY is normally secreted from distal L cells in the ileum and colon within 15 minutes of eating — before food has reached that part of the GI tract and likely thus due to neural pathways. The amount released is proportional to the number of calories consumed.10 Once released, it targets hypothalamic and brainstem nuclei that control appetite, resulting in decreased food intake.10 PYY rises most after high protein or high fat meals (but not high carbohydrate ones), though in obese individuals, the PYY increase is attenuated after these macronutrients.11 PYY also delays gastric and upper intestinal motility — the so-called "colonic brake" effect that reduces the rate of glucose absorption and thus the postprandial glycemic peak.12
In addition to its GI effects, PYY also has a role in muscle regeneration and repair. PYY and certain PYY receptors are expressed in both skeletal muscle and human muscle progenitor cells (hMPCs, i.e., adult muscle stem cells responsible for skeletal muscle repair, termed satellite cells in their dormant/resting state).13 The hMPCs can fuse with existing fibers to increase their size (hypertrophy, as seen in weight-bearing exercise) or fuse together to make new muscle fibers (proliferation/repair, after muscle damage).14 In addition, intramuscular PYY rises in low-energy states, (such as energy deficits), implying it has a role in skeletal muscle regeneration and repair.13
Importantly, people with sarcopenia exhibit significantly reduced levels of GLP-1, and treatment of myoblasts with GLP-disrupted the myogenic differentiation, perhaps contributing to sarcopenia.15 This may explain the magnitude of the muscle loss associated with GLP-1 RA treatment.15
In Summary
As an agent that activates TAS2Rs on both L and I enteroendocrine cells, Amarasate has been shown to cause significant increases in (at least) three anorexigenic GI hormones/peptides.1 Importantly, this has translated to significant weight loss over a 24-week period.2 While the weight loss achieved doesn't compete with that of semaglutide, tirzepatide, or retatrutide, it does surpass 5% when adjusted for the gain in skeletal muscle Amarasate produced, and occurred with minimal adverse effects (with only one participant in both the treatment and placebo arms withdrawing because of side effects).2
Kuhre et al note that endogenous GLP-1 stores are "substantial" and are rarely depleted.4 As an agent that leverages this store via stimulation of GLP-1 release from L cells, Amarasate has shown not only that it supports significant weight loss but also preserves muscle mass, likely through co-secretion of PYY from those EECs, which then acts on skeletal muscle PYY receptors. The PYY also contributes to the anorectic effect of Amarasate, as does CCK, released in response to activation of TAS2Rs on I cells.
- Activates brain appetite control centres
- Slows down stomach emptying
- Activates brain appetite control centres
- Slows down stomach emptying
- Stimulates leptin release from fat cells
- Aids in fat digestion
- Activates brain appetite control centres
- Slows down stomach emptying
- Involved in repair and growth of muscle fibres
Amarasate has thus proven to be an effective addition to the weight management toolbox. This triple-hormone therapy can be used both as an alternative to GLP-1 RAs and as an "off-ramp" and maintenance treatment for individuals stopping the medications. Amarasate can also be used as a complementary agent taken concurrently with GLP-RAs, providing a counter to the muscle-loss effects that occur with them, and to the decrease in endogenous GLP-1 that the medications produce.16
