Homeostasis - 9.4

Although no single brain region has exclusive control of appetite, twentieth-century research established that the hypothalamus is critically important for regulating metabolic rate, food intake, and body weight. In this classic research, scientists found that lesions in the hypothalamus of rats could induce either chronic hunger and massive weight gain, or chronic satiety (feeling full) and severe weight loss, depending on the location of the lesion.

RESEARCHERS AT WORK

Lesion Studies Showed That the Hypothalamus Is Crucial for Appetite

Early researchers made discrete bilateral lesions in the hypothalamus—in either the ventromedial hypothalamus (VMH) or the lateral hypothalamus (LH)—of rats (FIGURE 9.13). After recovery, VMH-lesioned rats ate to excess and became obese (Hetherington and Ranson, 1940), leading researchers to suggest that the VMH is the satiety center of the brain (because the rats didn’t show evidence of satiety once the VMH was gone). Rats with LH lesions, conversely, ceased eating and rapidly lost weight, suggesting that the LH acts as a hunger center (because rats who lost their LH stopped acting hungry) (Anand and Brobeck, 1951). So, an early model of feeding behavior featured the VMH and LH acting in opposition to control appetite.

FIGURE 9.13 Lesion Studies Revealed That the Hypothalamus Is Involved in Appetite View larger image

It soon became clear that this dual-center model of appetite was too simple. For one thing, although the VMH was identified as a satiety center, its destruction did not create out-of-control feeding machines. Instead, VMH-lesioned animals exhibited a period of rapid weight gain but then stabilized at a new, higher level. When obese VMH-lesioned animals were forced to either gain or lose weight through dietary manipulation, they returned to their new “normal” weight as soon as they were allowed to eat freely again. Therefore, because VMH-lesioned rats experienced satiety, the VMH cannot be the sole satiety controller.

Similarly, although they initially stopped eating, LH-lesioned rats that were kept alive with a feeding tube soon resumed eating and drinking, and their body weight eventually stabilized at a new, lower level. As with the VMH-lesioned animals, LH-lesioned animals that were later forced to gain weight would swiftly return to their new, lower set point for body weight after they returned to eating at will (see Figure 9.13). Researchers thus realized that the hypothalamic system controlling feeding must involve multiple components that coordinate to establish a set point for metabolic fuels, monitor energy balance in the body, and trigger behavioral responses to meet the established energy goals, with a collective effect on body weight.

By demonstrating that the hypothalamus contains distinct components of an appetite control network, the early work on hunger and satiety provided a framework for subsequent research. For example, fMRI studies show that activity increases in the hypothalamus when hungry people are given glucose (sugar) or amino acids, probably acting via specialized hypothalamic neurons that directly monitor blood levels of glucose (Nakamura et al., 2021). In fact, if you are hungry enough, simply viewing pictures of appetizing food reportedly causes activation in the hypothalamus and hunger-related areas (FIGURE 9.14) (Lizarbe et al., 2013)! Today it is clear that the hypothalamic control of feeding is quite complicated and, as we will see next, exhibits considerable redundancy as a safety measure.

FIGURE 9.14 Sweet Spot View larger image

Hormones from the body reflect long- and short-term energy reserves

A spate of discoveries has sharpened our understanding of the hypothalamic control of appetite. This evidence indicates that a circuit within the arcuate nucleus of the hypothalamus is the key element in a highly specialized appetite network integrating peptide hormone signals from several sites in the body. One important source of information about energy stores is the pancreas; we have already discussed how the pancreatic hormone insulin signals the state of glucose circulating in the blood. Other information about energy balance—especially short-term and long-term reserves—comes in the form of hormonal secretions from elsewhere in the body, particularly the digestive organs and fat tissue.

You may be surprised to learn that the fat cells that make up adipose tissue are endocrine; in fact, they release a hormone called leptin (from the Greek leptos, “thin”) into the bloodstream (Y. Zhang et al., 1994). Multiple types of leptin receptors (named LepRa through LepRf) are found throughout the brain, including the cortex and several nuclei of the hypothalamic appetite network that we will discuss shortly (Wada et al., 2014). Mutations that result in defective leptin receptors cause morbid obesity in lab animals (Roh et al., 2018; Zabeau et al., 2019) and in humans (Niazi et al., 2018). Likewise, genetically modified mice that fail to produce leptin rapidly become obese (FIGURE 9.15). Experiments with leptin signaling therefore tell us that the brain monitors circulating leptin levels as an indicator of the body’s longer-term energy reserves in the form of fat. Defective leptin production or impaired leptin sensitivity causes a false underreporting of body fat and leads to overeating, especially of high-fat or sugary foods.

FIGURE 9.15 Inherited Obesity Can Be Overcome View larger image

Shorter-term energy balance—the presence or absence of food in the gut—is reported by numerous hormones from the digestive organs. One of these hormones—ghrelin, synthesized and released into the bloodstream by endocrine cells of the stomach—reaches high concentrations during fasting and powerfully stimulates appetite (Smith and Moran, 2021), dropping sharply after a meal is eaten (Müller et al., 2015). Experimental manipulations of ghrelin activity in the brains of hamsters alter their foraging and feeding behaviors, illustrating the importance of ghrelin for stimulating food intake (M. A. Thomas et al., 2016). In addition, ghrelin reportedly acts via the hippocampus and hypothalamus to directly integrate with cognitive processes—such as memory—that influence meal size decisions (Suarez et al., 2020).

If ghrelin serves as a hunger signal, several intestinal hormones are candidate satiety signals. For example, the actions of the awkwardly named intestinal peptide PYY3-36 may be the converse of ghrelin’s actions, with PYY3-36 spiking to higher levels on ingestion of a meal and providing an appetite-suppressing signal (Karra et al., 2009; Alhabeeb et al., 2021). Injections of ghrelin cause increased appetite and feeding in rats or humans, and injections of PYY3-36 into the bloodstream or directly into the arcuate nucleus curb appetite (Price and Bloom, 2014). Furthermore, ghrelin is chronically slightly elevated in obese people, and PYY3-36 is chronically lowered—possibly causing continual hunger (English et al., 2002; Naznin et al., 2015).

Like PYY3-36, the intestinal hormone glucagon-like peptide 1 (GLP-1) shows a rapid increase during a meal, especially if the meal is high in fats and carbohydrates. The release of GLP-1 is initially governed by a rapid autonomic neural mechanism, and then by the presence of nutrients in the intestinal tract (E. W. L. Sun et al., 2019). Receptors for GLP-1 are found in several brain regions implicated in food intake (Knudsen et al., 2016; Burmeister et al., 2017), mediating reductions in appetite and feeding, along with changes in the system that signals the rewarding aspects of food (Sekar et al., 2017; Yang et al., 2017). In addition, GLP-1 activity directly blocks the effects of ghrelin on metabolism and appetite (Abtahi et al., 2019).

The discoveries of PYY3-36, ghrelin, and GLP-1 have provided important clues about the appetite control mystery, and these hormones converge on an appetite controller in the arcuate nucleus, so next we’ll have a look at how that system seems to work.

A hypothalamic appetite system integrates hormonal inputs to regulate hunger and satiety

A simplified (yes, trust us) view of the organization of the appetite control circuitry in the hypothalamus is illustrated in FIGURE 9.16. Within the arcuate nucleus, the system relies on two types of neurons with opposite effects. POMC/CART neurons act as satiety neurons when activated, inhibiting appetite and increasing metabolism. However, neighboring NPY/AgRP neurons act as hunger neurons when they are activated, stimulating appetite directly and also inhibiting the POMC/CART neurons (thereby blocking satiety signals) and reducing metabolism. (In case you are wondering, these neurons get their cumbersome names from the signaling compounds they produce: pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript in the case of POMC/CART neurons and, for NPY/AgRP neurons, neuropeptide Y and agouti-related peptide. These sorts of details are why graduate school takes so long.)

FIGURE 9.16 An Appetite Controller in the Hypothalamus View larger image

So how do the peripheral hormone signals interact with the arcuate-based appetite controller depicted in FIGURE 9.16B? As we’ve discussed, leptin levels (and to a lesser extent, insulin levels) in the blood convey information about the body’s longer-term energy reserves, stored in fat cells. Leptin affects both types of arcuate appetite neurons, but in opposite ways. High circulating levels of leptin activate the POMC/CART satiety neurons and simultaneously inhibit the NPY/AgRP hunger neurons—so in both ways leptin is working to suppress hunger, and selective deletion of the leptin receptors on NPY/AgRP neurons causes mice to rapidly become obese (Xu et al., 2018).

In contrast to leptin, the gut hormones that we discussed earlier—particularly ghrelin, PYY3-36, and GLP-1—provide shorter-term, hour-to-hour hunger signals from the gut. Ghrelin and PYY3-36 act primarily on the appetite-stimulating NPY/AgRP neurons of the arcuate nucleus. In this model, ghrelin stimulates these cells, leading to a corresponding increase in appetite, while PYY3-36 works in opposition, inhibiting the same cells to reduce appetite. Short-term effects on appetite exerted via the NPY/AgRP neurons therefore reflect a balance between ghrelin and PYY3-36 activity. In contrast, GLP-1 acts on the appetite-reducing POMC/CART cells of the arcuate nucleus, resulting in a reduction in appetite and food intake (Grill, 2020; Smith and Moran, 2021), directly opposing the appetite-enhancing actions of the NPY/AgRP system.

The net result of all these processes is a constant balancing act between the appetite-stimulating effects of the NPY/AgRP system and the appetite-suppressing