Obesity is a widespread and serious health concern, often leading to comorbidities such as type 2 diabetes. While diet and lifestyle adjustments are frequently recommended, they can be challenging to maintain and may not always be effective in the long run. The exploration of alternative therapeutic options is therefore essential. High-protein diets (HPDs) have been linked to increased satiety and weight loss compared to diets rich in other macronutrients. The precise mechanisms behind the effects of HPDs remain unclear, but evidence suggests that the sensing of amino acids, resulting from protein digestion, may play a role in appetite regulation and satiety. One such amino acid, L-phenylalanine (L-Phe), has garnered attention for its potential role in weight management.
What is Phenylalanine?
Phenylalanine is an amino acid, the building block of protein. There are three forms: L-, D-, and DL-phenylalanine. L-phenylalanine is an essential amino acid found naturally in foods like meat and eggs. It is the only form of phenylalanine found in proteins. D-phenylalanine is not an essential amino acid, and its role in the body is not currently understood. DL-phenylalanine is made in a lab.
L-phenylalanine is an essential, aromatic amino acid required for protein synthesis in humans and is hydroxylated to L-tyrosine in the liver. L-phenylalanine is not found in its free form in the diet but occurs exclusively in a bound form as a component of proteins or peptides. Good vegetable sources of L-phenylalanine include pumpkin seeds, walnuts, and wholemeal wheat flour. L-tyrosine is the precursor of the excitatory neurotransmitters dopamine, norepinephrine, and adrenaline (catecholamines) and the thyroid hormones thyroxine and triiodothyronine. It is involved in neurovegetative processes and all metabolic processes. Phenylethylamine (PEA) can also be synthesized from phenylalanine through a one-step metabolic pathway alternative to catecholamines. PEA itself is not a catecholamine but acts as a stimulatory neurotransmitter. The synthetically produced D-form of phenylalanine cannot be used for metabolism.
L-Phenylalanine's Potential Role in Weight Loss
L-phenylalanine can be used as an adjuvant in comprehensive obesity treatment. L-phenylalanine supports the production of the peptide cholecystokinin (CCK), which is involved in triggering the feeling of satiety. The intake of 10 g L-phenylalanine, D-phenylalanine or a placebo 20 min before a standard meal with a known number of calories led to an increase in basal cholecystokinin levels in a human study. Participants who received L-phenylalanine consumed almost 500 kcal less than people taking placebo. In addition, the L-PA group reported a significantly higher feeling of satiety.
Specific l-amino acids, including l-Phe, stimulate the release of the energy and glucose homeostasis-regulating gut hormones peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide from isolated rat small intestine through a CaSR-dependent mechanism.
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Effects on Appetite and Food Intake
Research suggests that L-Phe may influence appetite and food intake through various mechanisms. Studies in rodents have shown that oral administration of L-Phe can acutely reduce food intake in rats and mice and chronically reduce food intake and body weight in diet-induced obese mice. Ileal L-Phe also reduced food intake in rats.
One study conducted by the Department of Gastroenterology at St. Bartholomew’s Hospital in London found that administering L-phenylalanine to participants before meals reduced food intake and increased levels of cholecystokinin (CCK), a hormone that stimulates digestion and helps keep appetite under control.
Modulation of Gut Hormones
L-Phe has been shown to stimulate the release of GLP-1 and PYY while reducing plasma ghrelin levels in rodents. These gut hormones play crucial roles in appetite regulation, satiety, and glucose homeostasis. GLP-1 and PYY are highly expressed in the ileum, suggesting the ileum may contribute to the greater satiety observed following a high-protein meal.
Oral L-Phe administration significantly increased plasma GLP-1 levels and reduced plasma acylated ghrelin levels in rats.
Impact on Energy Expenditure and Metabolism
L-Phe may also influence energy expenditure and metabolism. In rats, L-Phe increased maximal oxygen consumption (VO2) and maximal carbon dioxide production (VCO2). The respiratory exchange ratio was also lower in L-Phe-treated rats.
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Role of the Calcium-Sensing Receptor (CaSR)
L-Phe is a potent agonist of the CaSR, which has been implicated in amino-acid-induced gut hormone release in vitro. CaSR is highly expressed and co-localized within GLP-1 and PYY-secreting L cells. The expression of CaSR was detected in all levels of the GI tract in mice. Studies suggest that the anorectic effect of L-Phe may be mediated via the CaSR. Oral administration of the synthetic CaSR agonist R568.HCl significantly reduced food intake.
The anorectic effect of intra-ileal administration of L-Phe was attenuated by the co-administration of NPS2143.HCl, a CaSR antagonist.
L-Phenylalanine and Glucose Homeostasis
L-Phe has demonstrated potential benefits for glucose homeostasis. In rats, L-Phe stimulated insulin release and improved glucose tolerance. Oral administration of L-Phe significantly lowered plasma glucose levels following an intraperitoneal glucose tolerance test (IPGTT) in rats.
L-Phenylalanine and Exercise
When combined with exercise, dietary amino acid (AA) supplementation is an effective method for accelerating fat mobilization. Pre-exercise ingestion of L-phenylalanine significantly accelerated glucagon secretion during both rest and exercise, and serum glycerol levels increased significantly during exercise, indicating a shift towards fat oxidation.
Other Uses of Phenylalanine
People use phenylalanine for a disorder that causes white patches to develop on the skin (vitiligo). It is also used for attention-deficit hyperactivity disorder (ADHD), chronic pain, aging skin, depression, and many other purposes, but there is no good scientific evidence to support most of these uses.
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Uses & Effectiveness
Possibly Effective for
- A skin disorder that causes white patches to develop on the skin (vitiligo). Taking L-phenylalanine by mouth, or applying it to the skin, both in combination with UVA light, seems to improve symptoms of vitiligo.
Possibly Ineffective for
- Attention deficit-hyperactivity disorder (ADHD). Taking phenylalanine by mouth doesn't seem to help ADHD.
- Chronic pain. Taking D-phenylalanine by mouth does not seem to reduce pain.
Safety and Side Effects
L-phenylalanine is commonly consumed in foods. L-phenylalanine, D-phenylalanine, and DL-phenylalanine are possibly safe when used as medicine, short-term. Side effects might include anxiety, headache, and constipation. Phenylalanine cream is possibly safe when used short-term when applied to the skin.
Special Precautions and Warnings
- Pregnancy: Having too much phenylalanine during pregnancy can increase the chance of birth defects. For patients who process phenylalanine normally and have normal levels, it is fine to consume phenylalanine in typical food amounts, but supplements containing phenylalanine should be avoided. For pregnant patients who have high levels of phenylalanine, such as those with a condition called phenylketonuria (PKU), even normal food amounts are unsafe. For these patients, experts recommend a low phenylalanine diet for at least 20 weeks before getting pregnant. This should reduce the risk of birth defects.
- Breast-feeding: There isn't enough reliable information to know if any form of phenylalanine is safe to use in larger amounts as medicine while breast-feeding. Stay on the safe side and avoid use.
- Phenylketonuria (PKU) and other conditions that cause high levels of phenylalanine: Some people have inherited disorders, such as PKU, that cause their bodies to build up too much phenylalanine. This can cause developmental delay, high blood pressure, stroke, and many other serious health issues. If you have one of these disorders, avoid phenylalanine supplements.
- Schizophrenia: Some people with schizophrenia have a movement disorder called tardive dyskinesia. Phenylalanine might make this movement disorder worse.
Interactions
- Moderate Interaction: Be cautious with this combination.
- Levodopa is used for Parkinson's disease. Taking phenylalanine along with levodopa can make Parkinson's disease worse. Do not take phenylalanine if you are taking levodopa.
- Phenylalanine can increase a chemical in the body called tyramine. Large amounts of tyramine can cause high blood pressure. Some medications used for depression stop the body from breaking down tyramine. Some common MAOIs include phenelzine (Nardil), selegiline (Zelapar), and tranylcypromine (Parnate).
- Phenylalanine might decrease how much baclofen the body absorbs. This might decrease the effects of baclofen.
Dosage
L-phenylalanine is an essential amino acid found in foods including meat, fish, eggs, cheese, and milk. As medicine, L-phenylalanine, D-phenylalanine, and DL-phenylalanine have been used in varying doses. L-phenylalanine has most often been used by adults in doses of 250 mg or 100 mg/kg by mouth daily for up to 3 months. Speak with a healthcare provider to find out what form and dose might be best for a specific condition.
Lac-Phe: A Metabolite Link Between Exercise and Appetite
A team of researchers recently investigated the issue using a metabolomics approach, i.e. by studying the expression of all the metabolites following vigorous exercise sessions (running). The metabolite N-lactoyl-phenylalanine was first identified a decade ago, but until recently its function was unknown. Lac-Phe is produced from lactate, which is generated in muscle cells during vigorous exercise and then released into the bloodstream, and the amino acid phenylalanine. The formation of this metabolite is catalyzed (i.e., greatly accelerated) by the CNDP2 enzyme, which is expressed in several cell types (e.g., immune system cells, epithelial cells).
Daily administration of Lac-Phe caused obese mice to lose 7% of their body mass after 10 days, reduced adiposity, and improved blood sugar control. The activity level of the mice remained normal, but they simply ate less food (-50% over a 12-h period). Curiously, the administration of Lac-Phe to lean mice had no effect on their appetite.
Researchers looked at Lac-Phe levels in healthy people before and after exercising in two independent cohorts. In a first cohort of 36 people, Lac-Phe was the third metabolite that increased the most after exercising. Participants in the second cohort participated in three distinct types of exercise: sprint (maximum-intensity cycling), endurance (moderate-speed cycling), and resistance (strength training). Lac-Phe levels increased after all three types of exercise.
It is not yet known whether Lac-Phe decreases appetite in humans as it does in mice; this remains to be demonstrated. Researchers hope to one day be able to produce a drug based on Lac-Phe that could decrease the appetite of obese people who cannot exercise due to other health problems. However, dietary supplement enthusiasts should be aware that Lac-Phe is completely inactive when taken orally.
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