Metabolics and Appetite Regulation

Appetite Regulation

The brain plays an important role in food intake, energy expenditure and body weight regulation. The gut controls the brain's feeding behaviour via hunger and satiety signals. These signals are mediated by two opposing hormones – ghrelin and leptin – which interact with the central melanocortin system.

Ghrelin is commonly called the 'hunger hormone' as it stimulates appetite, increases food intake and promotes fat storage, via receptors in the brain. As ghrelin is under circadian control, it is higher in the morning (daylight), prompting food seeking (foraging) behaviour.

Leptin is the 'satiety hormone' which inhibits hunger after eating and stimulates metabolism. Levels are higher in the evening (darkness) and when they drop the brain interprets this as a loss of energy and hunger increases.

In summary, ghrelin is associated with a low energy, fasted state and leptin with a high energy, fed state.

Low Energy, Fasted

FTO (fat mass and obesity-associated protein) is commonly called the 'fat gene' due to its connection with increased appetite. It is highly expressed in the brain as well as the heart, kidneys and fat cells. Over-expression of FTO, due to genetic variance, is associated with lower leptin levels, higher ghrelin levels, and an increased preference for calorie-dense (sweet and high fat) foods. A SNP on FTO has been consistently associated with higher body fat, BMI, waist circumference and obesity (on average 3kg heavier). Rhubarb and green tea are both FTO inhibitors.

Cannabinoids promote ghrelin, food intake and energy accumulation. FAAH (fatty acid amide hydrolase) metabolises endogenous cannabinoids including AEA (N- arachidonoylethanolamine, known as anandamide) and 2-AG (2-arachidonoylglycerol) which are involved in the perception of pain, regulation of appetite and immune system function. A SNP on FAAH has lower activity and thus increased levels of cannabinoids. This can confer increased appetite (higher ghrelin), food intake and weight gain. Limit intake of omega-6 fats which can increase cannabinoid levels, ghrelin driven foraging behaviour (snacking), and risk of over-eating. Oleic acid, in olive oil, can help to regulate cannabinoids and ghrelin.

NPY (neuropeptide Y) and AgRP (agouti-related peptide) promote food consumption and energy accumulation. They are stimulated by ghrelin and inhibit the melanocortin pathway (via MC4R), which together increase appetite. Conversely, when energy is higher after eating, neurons that express POMC (proopiomelanocortin) are recruited to antagonise the actions of NPY and AgRP to reduce food intake and stimulate metabolism. AgRP and POMC neurons compose a unique neural circuit known as the melanocortin system.

The NPY gene is expressed in the central nervous system and influences many processes, including stress response, food intake, circadian rhythms, and cardiovascular function. A SNP confers significantly higher NPY and AgRP activity, increased appetite and decreased energy expenditure. This is associated with more 'foraging' behaviour towards food and alcohol, and greater risk of obesity and metabolic dysfunction. NPY is increased in obesity, which can result in a vicious cycle. It is also associated with maladaptive responses to stress (over or under-eating).

The conclusion of this pathway is hunger.

High Energy, Fed

Leptin interacts via its receptor LEPR in the brain, tells it there is enough energy, and sends the message of satiety and suppression of hunger. As adipocytes (fat cells) produce leptin, greater adiposity (fatness) results in higher leptin levels. This can lead to 'leptin resistance' (loss of sensitivity of the receptor) so one never feels full. Variances on the LEPR gene can have the same effect – lower sensitivity to leptin and reduced satiety. Leptin sensitivity can be increased with omega-3 fatty acids, exercise and sleep.

After activation by leptin, the POMC protein is cut into smaller pieces including MSH (melanocortin) peptides. A SNP on POMC can result in a shorter version of the protein and fewer MSH peptides and less binding to MC4R (melanocortin-4 receptor), resulting in greater interest in food and impaired satiety. A high protein diet including tryptophan (in chicken and almonds) and olive oil can increase POMC and help reduce appetite. Serotonin activates POMC, resulting in similar satiety effects as leptin. In addition to negative impacts on mood and mental health, low serotonin has been linked to weight gain, obesity and diabetes. Insulin is also an inducer of POMC, while palm oil inhibits it.

MC4R is an important regulator of energy homeostasis, food intake and body weight via its binding to BDNF (brain-derived neurotrophic factor). A SNP on MC4R indicates a less sensitive receptor, and weaker satiety signalling and metabolism. It is the single most impactful genetic polymorphism predisposing to obesity. Carriers should limit portion size of meals, choose smaller plates and avoid the buffet (and seconds).

BDNF promotes growth, differentiation and survival of neurons and synapses in the central and peripheral nervous systems. In the melanocortin system, BDNF plays an essential role in regulating appetite and energy balance. A SNP can reduce its activity and increase the risk of obesity. BDNF can be increased by intense exercise, vitamin D, curcumin, green tea, omega- 3-fatty acids and resveratrol. The neurotransmitter dopamine also plays a role in controlling eating behaviours, by activating the melanocortin neuron.

The conclusion of this pathway is satiety.

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