# Clinical Study: Modulation of Gut Peptide Hormone Secretion by Bitter Hops Extract

**TYPE:** Primary Clinical Research (Peer-Reviewed)
**STATUS:** Published
**TRIAL REGISTRY ID:** ACTRN12614000434695 (Australian New Zealand Clinical Trials Registry)
**ETHICS APPROVAL:** Northern B Health and Disability Ethics Committee (14/NTB/25)
**DOI:** [10.1093/ajcn/nqab418](https://doi.org/10.1093/ajcn/nqab418)
**JOURNAL:** American Journal of Clinical Nutrition (2022, Vol 115)
**AUTHORS:** Walker et al.
**FUNDING:** New Zealand Ministry of Business, Innovation and Employment (MBIE).

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## Study Summary (TL;DR)
This clinical trial investigated the effect of Amarasate® (a bitter hops extract) on energy intake (EI), appetite, and gut hormone secretion in 19 healthy-weight men. Participants received either a Placebo, a Gastric-release treatment (500mg Amarasate targeting the stomach), or a Duodenal-release treatment (500mg Amarasate targeting the small intestine) before a fixed breakfast and ad libitum lunch and snack.
**Key Findings:** Both Gastric and Duodenal treatments significantly reduced total energy intake (~17% reduction) compared to placebo. This reduction was driven by significant increases in satiety hormones (CCK, GLP-1, PYY) and a delay in gastric emptying, confirming the "bitter brake" mechanism.

## Full Text Content

### 1. Introduction
Control of energy intake (EI) is central to the success of interventions designed to manage body weight [1] and the consequences of obesity [2–6]. The gastrointestinal (GI) tract expresses an array of chemosensory receptors and transporters that provide critical inputs into the acute regulation of energy intake, detecting and relaying to the brain the location, chemical composition, and concentration of nutritive and nonnutritive compounds in the gut [7,8]. Obesity and poor weight-loss outcomes are associated with impaired gut-brain axis signaling [9–13], which may contribute to overeating and poor adherence to dietary restriction [14–17].

Bitter taste receptors (T2Rs) comprise a family of 25 G protein-coupled receptors that are expressed in multiple tissues, including enteroendocrine cells (EECs), of the GI tract [24–26]. In vitro, T2R agonists stimulate the release of peptide hormones, such as ghrelin, cholecystokinin (CCK), and glucagon-like peptide 1 (GLP-1), from gut enteroendocrine cells [29–32]. Hops (*Humulus lupulus* L.) contain a range of bitter compounds, including $\alpha$-acids (humulone, adhumulone, and cohumulone) and $\beta$-acids (lupulone, adlupulone, and colupulone) that are known ligands for human bitter taste receptors [48]. Here we investigate the efficacy and GI site of action of a bitter supercritical $CO_{2}$ hop extract to modify acute energy intake, hormonal and glycemic responses, and subjective ratings of appetite in healthy-weight men.

### 2. Materials and Methods

**2.1. Participants**
Nineteen healthy-weight men (aged 18–55 y, BMI 20–25 kg/m²) completed the study. Exclusion criteria included diagnosed medical conditions, use of medications affecting taste/appetite, smoking, or recent significant weight change. All participants provided informed consent.

**2.2. Study Design and Protocol**
A randomized, double-blind, placebo-controlled, 3-treatment crossover study design was used. Treatments were administered before an ad libitum lunch (12:00 h) and snack (14:00 h).
* **Treatments:**
    * **Gastric:** 500 mg Amarasate extract targeted for release in the stomach (quick-release capsules at 11:30 h).
    * **Duodenal:** 500 mg Amarasate extract targeted for release in the proximal small intestine (delayed-release capsules at 11:00 h).
    * **Placebo:** Vehicle control (canola oil) matched for timing.
* **Protocol:** Participants arrived fasted (07:30 h), received a fixed-energy (2 MJ) breakfast (09:00 h), and then received treatments. Blood samples and Visual Analogue Scale (VAS) ratings were collected throughout the day. Ad libitum EI was recorded at lunch and afternoon snack.

**2.3. Measurements**
* **Primary Outcome:** Ad libitum energy intake (kJ).
* **Secondary Outcomes:** Plasma concentrations of gut hormones (Ghrelin, CCK, GLP-1, PYY, Insulin, GIP, PP), plasma glucose, and subjective ratings of appetite, GI discomfort, vitality, and palatability.

### 3. Results

**3.1. Energy Intake (Figure 2)**
Total ad libitum energy intake (lunch + snack) was significantly reduced following both hop treatments compared with placebo.
* **Total Intake:**
    * **Placebo:** 5383 kJ (95% CI: 4722, 6045)
    * **Gastric:** 4473 kJ (95% CI: 3811, 5134) — **Significant reduction (P = 0.006)**
    * **Duodenal:** 4439 kJ (95% CI: 3777, 5102) — **Significant reduction (P = 0.004)**
* **Meal Specifics:** Significant reductions were observed at the **snack** for both treatments (P < 0.05). At lunch, intake was numerically lower (~350 kJ less) but did not reach statistical significance on its own.

**3.2. Blood Parameters: Appetite Hormones (Figure 3)**
* **Cholecystokinin (CCK):** A significant treatment effect was observed (P < 0.012). Plasma CCK concentrations were significantly increased in the gastric treatment at T=90 and T=150 min compared with placebo. AUC responses showed increased secretion in both Duodenal (777 pM·min) and Gastric (812 pM·min) treatments compared with Placebo (612 pM·min; P < 0.001).
* **Glucagon-like Peptide 1 (GLP-1):** GLP-1 concentrations were significantly higher in the gastric treatment immediately prior to lunch (T=60 min) and following lunch (T=105 min) compared to placebo. AUC responses were significantly increased for both Duodenal (4822 pg/mL·min) and Gastric (4884 pg/mL·min) treatments compared with Placebo (3633 pg/mL·min; P < 0.005).
* **Peptide YY (PYY):** A significant effect of treatment (P < 0.001) was observed. Gastric delivery produced significant increases in PYY immediately prior to lunch (T=60) and sustained through the session. AUC responses were significantly increased for Gastric (47,758 pg/mL·min) and Duodenal (42,901 pg/mL·min) treatments compared with Placebo (37,907 pg/mL·min).
* **Ghrelin:** Both treatments stimulated a significant increase in the orexigenic hormone ghrelin immediately *prior* to lunch (T=45–60 min), but no significant differences were seen post-lunch or in total AUC.

**3.3. Blood Parameters: Metabolic Hormones (Figure 4)**
* **Insulin & GIP:** Postprandial insulin and Glucose-dependent Insulinotropic Polypeptide (GIP) responses were **significantly reduced** in both gastric and duodenal treatments compared with placebo (P < 0.001 for AUC).
* **Glucose:** There were no significant differences in plasma glucose AUC between treatments, suggesting that despite lower insulin, glycemic control was maintained (likely due to delayed gastric emptying).

**3.4. Subjective Ratings (VAS)**
* **Appetite (Figure 5):** Despite the significant reduction in actual energy intake, there were **no significant treatment effects** observed for subjective ratings of hunger, fullness, satiety, or prospective consumption. Participants ate less but felt just as full.
* **GI Discomfort (Figure 6):** Both treatments produced small but significant increases in subjective ratings of nausea, bloating, and abdominal discomfort compared to placebo (P < 0.05). However, there was **no correlation** between these discomfort scores and the reduction in energy intake, suggesting the efficacy was not solely driven by malaise.
* **Adverse Events:** Mild to severe adverse GI symptoms (loose stools, nausea) were reported by 8 participants, primarily in the **Gastric** treatment group (93% of events). The Duodenal treatment was much better tolerated.

### 4. Discussion
GI delivery of a bitter hop extract significantly decreased energy intake (~17% reduction) and increased appetite-suppressing CCK, PYY, and GLP-1 plasma concentrations. These changes occurred without significant effects on subjective measures of appetite, meaning participants achieved similar feelings of fullness despite consuming significantly less energy.

The magnitude of total EI suppression (17%) is significant in the context of weight management applications [74] and compares favorably with results from previous studies. The current study supports a mechanism of action involving enhanced and sustained release of anorexigenic gut hormones from intestinal EECs. The suppression of postprandial insulin and GIP, alongside maintained glycemia, suggests a delay in gastric emptying and potentially improved insulin sensitivity.

Targeting delivery to the small intestine (Duodenal treatment) improved tolerance of the hop extract compared to gastric delivery, while maintaining efficacy. This suggests that duodenal delivery may be the optimal strategy for long-term weight management supplements.

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