Genetics can predispose individuals to obesity. At least 32 single nucleotide polymorphisms (SNPs) have been associated with obesity risk; they might increase obesity risk by modulating appetite and incretins (metabolic hormones that promote a decrease in blood glucose).
This paper consisted of two studies: a crossover randomized controlled trial (RCT) and an observational study. For both studies, buccal (inner cheek) swabs were collected to assess the participants’ CYP1A2 genotype. The CYP1A2 gene encodes cytochrome P4501A2, the enzyme responsible for >95% of caffeine metabolism: people with the AA genetic variant are “fast” metabolizers; people with the AC genetic variant are “intermediate” metabolizers; and people with the CC genetic variant are “slow” metabolizers.
In the crossover RCT, 18 healthy people completed two experimental protocols. Before each protocol, they abstained from caffeine for seven days. For each protocol, they first ate a standardized breakfast; immediately after, they drank either 200 mL of water or 200 mL of filtered coffee providing 5 mg of caffeine per kilogram of body weight; and for lunch, three hours later, they ate as much food as they wanted within 30 minutes. Blood samples were collected immediately before breakfast and lunch to assess satiety hormones (asprosin and leptin).
The primary outcomes were the effects of coffee intake and caffeine genotype on caloric intake at the ad libitum lunch. The secondary outcomes were the effects of coffee intake and caffeine genotype on macronutrient intake, satiety hormones, and subjective appetite and satiety at the ad libitum lunch.
When people think about hormones related to appetite, they typically think of leptin, ghrelin, PYY, or glucagon-like peptide-1 (GLP-1). Asprosin is a newfound appetite-stimulating hormone, having been discovered in 2016 in a study of neonatal premature aging (NPS) patients. These patients, who lack asprosin, ate less than people without the condition and were extremely lean.
Asprosin is an adipokine — a type of cell-signaling protein produced by adipose tissue. It acts on the hypothalamus to promote appetite and on the liver to stimulate glucose production. Some evidence suggests that asprosin levels are higher in people with obesity. However, since asprosin is a recent discovery, more research is needed to determine its clinical significance.
In the observational study, 284 people were categorized as having a high, medium, or low obesity genetic risk score (Ob-GRS), based on 32 SNPs identified previously. They completed a questionnaire assessing diet, appetite, physical activity, lifestyle factors, and coffee intake (in cups per week; each cup was assumed to contain 200 mg of caffeine). They were asked to choose among the following statements:
Coffee intake suppresses my appetite.
Coffee intake has no effect on my appetite.
Coffee intake elevates my appetite.
Do not know.
In the crossover RCT, rapid metabolizers had lower asprosin levels and ate fewer calories and less dietary fat than slow and intermediate metabolizers. Leptin levels didn’t differ between caffeine genotypes.
In the observational study, coffee reduced the subjective appetite of 56.9% of rapid metabolizers, 48.3% of intermediate metabolizers, and 43.7% of slow metabolizers. Moreover, in people with a high Ob-GRS, high coffee intakes were associated with a lower BMI in rapid metabolizers than in low and intermediate metabolizers.
The big picture
This is the first study to assess the relationship between CYP1A2 genotype, caffeine, and obesity risk. However, a 2017 observational study found that, among people with a genetic predisposition to obesity, those who consumed more than 3 cups of coffee per day had a lower risk of obesity than those who consumed less than 1 cup of coffee per day.
More research assessing the effects of CYP1A2 genotype on obesity risk is needed. However, several studies have assessed the effects of CYP1A2 genotype on caffeine’s ergogenic effects. A 2020 systematic review identified 11 such studies; of the only 2 that reported a difference in ergogenic effects between genetic variants, both favored rapid metabolizers.
CYP1A2 genotype can affect more than just body weight and exercise performance. Some evidence suggests that higher caffeine intakes increase the risk of insulin resistance, high blood pressure, and heart attacks in intermediate and slow but not rapid caffeine metabolizers.
CYP1A2 might not be the only gene that mediates caffeine’s effects. The ADORA2A gene codes for the adenosine A2A receptor, which is important because caffeine acts primarily by blocking adenosine receptors in the brain. While more research is needed to elucidate the clinical significance of ADORA2A, some evidence suggests that variations in ADORA2A genotype might mediate caffeine’s effects on sleep.
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