The biggest health burden worldwide is the increasing prevalence of obesity driving nutritional and medical research to explore the most effective strategies to tackle what is now an obesity pandemic. There are numerous factors that contribute to weight gain but ultimately by the law of thermodynamics, a body will gain weight when excess energy is consumed. Excess energy in the form of food which we call ‘overeating’, is the process of consuming more calories than we need (1).
At a very basic level, eating is driven by appetite, the desire to eat. Appetite has been an essential drive throughout human evolution and only until recently have we been more worried about eating enough rather than too much.
In recent times our environment has changed so much so that little competition to eat exists. In fact, the amount of energy needed to find and eat food is little to none. Our evolutionary drive and metabolism are not adjusted to the current environment leaving our biological hunger signals stuck in survival mode. This means keeping our desire to eat under control when food is so widely available is no easy task, and some have hunger drives greater than others.
If overeating is driven by appetite, what drives appetite?
Our understanding of appetite regulation and the mechanical circuits that govern appetite have vastly improved over recent years. The brain plays a central role in the regulation of appetite and located deeply within the brain is the hypothalamus which is responsible for maintaining homeostasis, the process of keeping our body in a balanced state, for example, feeding and fasting. The action of feeding and fasting is prompted by neurological signals driving us to eat or to fast (2).
The hypothalamus is located in the lower centres of the brain. The lower centres of the brain are where the most primitive and evolutionary important drives are located (3).
When exploring the hypothalamus in greater detail we can locate distinct areas which play a key role in appetite. The arcuate nucleus (AN) is commonly referred to as the sensing centre of the hypothalamus. It is located just above the median eminence which is a circumventricular organ (CVO), meaning it is an area of the brain that is in a privileged position to sample the periphery system. It has a more permeable blood-brain barrier allowing it to sense nutrients and other signals from the peripheral system, like the gut (4,5)
The key anatomical areas of the hypothalamus (K.Murphy & S.Bloom), and the lower region of the brain (J.Clasadonte & V.Prevot,2017). *Note, the AN is the terminology for this section of the brain in rodents but is actually called the infundibular nucleus (IFN) in humans. However, as papers and other lectures commonly refer to the human IFN as the AN, we'll stick with AN in this post for simplicity reasons.
The AN expresses two distinct and antagonistic types of neurons that feed to the higher centres of the hypothalamus, these neurons are categorised as:
Orexigenic peptide expressing neurons
Anorexigenic peptides expressing neurons
The AN will signal to other nuclei in the hypothalamus such as the lateral hypothalamus (LH) the ventromedial hypothalamus (VM) and the paraventricular nucleus (PVN) (6). In rodent models, lesions of the LH inhibits feeding and stimulation of the LH resulted in excessive feeding in already satiated mice (7). Conversely, lesions in the ventromedial hypothalamus (VMH) resulted in excessive eating and obesity (8). This early evidence indicated distinct functions of these nuclei in the regulation of appetite but our understanding has vastly improved over recent decades.
The AN secretes peptides to these higher brain centres to regulate appetite. The orexigenic peptides are appetite-stimulating peptides, meaning they signal to the higher centres in the hypothalamus to induce feeding. The key orexigenic peptides are neuro-peptide Y (NPY) and agouti-related peptide (AgRP). Conversely, the anorexigenic peptides are appetite suppressing peptides that signal to the higher centres to stop feeding and consequently feel full, such as pro-opiomelanocortin (POMC) and cocaine - and amphetamine-regulated transcript (CART) (6).
The neuropeptide mechanisms of action
Let's take the example of the POM-C pathway, POM-C splits to a potent anorexigenic peptide called a-melanocyte-stimulating hormone (a-MSH). The a-MSH is released from POMC axons in the AN which then binds to the melanocortin 3 and 4 receptors (MC3/4R) abundant in both the VMH and PV resulting in an inhibition of food intake (9). Stimulation of both MC3/4R hormones inhibits food intake (10).
The PVN expresses neurons that regulate the sympathetic outflow to peripheral organs, secreting neuroregulatory peptides (11). Lesions in the PVN leads to overeating and obesity and with the PVN being a target for different appetite-suppressing gut hormones, it seems its activity is predominantly involved in satiation (12). However, it is in the PVN where the orexigenic neuropeptides such as NPY & AgRP look to competitively inhibit a-MSH reception in the PVN, attenuating its satiety effect and stimulating appetite. Sparking another discussion are results from the genome-wide association study (GWAS) showing human patients with mutations in the Mc4r genes are more likely to be obese, potentially due to the lack of satiety signals (13).
The discovery & role of leptin in appetite & obesity
What controlled appetite was poorly understood until the discovery of leptin in the late 1980s. It was a recessive genetic mutation in the Ob gene in mice that caused uncontrollable hyperphagia, resulting in obesity. The Ob gene is responsible for the production of a hormone called leptin. Synthesised in fat cells, our leptin levels are directly proportional to the amount of body fat (14).
A control and leptin-deficient mouse. The discovery of leptin allowed scientists to better understand the influence of hormones like leptin on appetite, in addition to the mechanisms that help conduct the fine balancing act of energy intake and expenditure.
Leptin helps modulates energy balance by signalling to the hypothalamus to suppress appetite, depending on the bodies energy balance (15). If the body is in a prolonged period of negative energy balance, the evolutionary role of leptin kicks in. Leptin could play a role in hypothalamus amenorrhea (a state where the hypothalamus shuts down mensuration cycle) in a desperate attempt to conserve energy (16). When overweight humans lose weight, the neural activity in the hypothalamus responsible for increasing motivation to eat is enhanced following leptin administration, indicating that leptin could act as both an appetite suppressor and enhancer depending on the bodies energy balance (17).
The leptin receptor (LepRb) is expressed on both POMC and AgRP neurons, thought to be its route to modulating appetite and energy balance (18). Infusing Leptin in obese mice inhibited food intake and increased weight loss, prompting short-lived excitement for a potential solution to obesity (19). Unfortunately, these mechanisms were not replicated in humans following leptin administration in the obese, as the hypothalamus was resistant to the satiating signal from leptin (20). This proposes an interesting question as to whether obese individuals are born resistant to leptin, or whether obesity causes leptin resistance.
The role of gut hormones in appetite regulation & obesity
Glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK) and oxyntomodulin are four anorexigenic peptide hormones (amongst others) synthesised within the gastrointestinal tract (GI tract) that contribute to satiation via AN signalling (21). GLP-1 is widely expressed in the ARC and PVN and signals to the ARC which fires POMC and CART neurons to the PVN and higher centres of the brain while indirectly inhibiting NPY & AgRP (22). PYY is thought to act both directly on ARC and indirectly via vagal afferents and inhibits NPY by binding to the Y2 receptor of ARC while increasing the activity of POMC and a-MSH neurons, collectively resulting in satiation (23).
GLP-1 & PYY suppress appetite and reduce energy intake (Jack Penhaligan, 2019)
These hormones are secreted by L-cells which are a sub-group of enteroendocrine cells with a large amount of G-couple protein receptors (24). G-couple protein receptors are nutrient-sensing receptors, they sense the environment and then direct instructions through secreting gut peptides to the hypothalamus (25). Ghrelin, the only appetite-stimulating hormone we’re aware of is secreted in the stomach by P/D1 cells in the oxyntic glands. Ghrelin acts via the NPY pathway to increase energy intake by competitively inhibiting a-MSH reception in the PVN (26).
The brainstem & the nucleus of the solitary tract (NTS)
Within the brainstem is a pair of cells known as the nucleus of the solitary tract (NTS) which often get left out of the conversation when discussing appetite regulation. While the hypothalamus is involved with the more homeostatic processes, the brainstem and more specifically the NTS add another piece to this integrated and complicated appetite regulation puzzle. The NTS synthesises the anorexigenic peptide CCK (also secreted in the gut) which is activated following food consumption. Activating these neurons in mice resulted in significantly reduced food intake and weight loss.
Interestingly, the neurons within the NTS that express CCK form a connection with the PVN neurons that express MC4R receptors, indicating a potential route of action (27). In addition to this, the NTS also contains neurons that express both POMC and 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR), both involved in potent anorexigenic pathways (28). Although the direct role and interaction of the brainstem and how it communicates with the hypothalamus needs further research, there does seem to be integrative signalling circuits between the gut, brainstem and hypothalamus that's worth adding to the conversation (29).
Part 1 summary:
Granted, it's a lot of information to take in. Although I hope this has given you a nice understanding of the biological drives behind appetite and an appreciation for how amazing our body is. There's an extremely complicated and integrated system behind appetite and in part 2, we'll take a look at how we can manipulate our appetite signals to help manage obesity or to simply feel less hungry throughout the day.