Amylin interacts cooperatively with leptin. The anorexigenic effects of lepin when paired with amylin are greater than the sum of leptin and amylin’s independent anorexigenic effects. In other words, there is a greater-than-additive effect on satiety when leptin and amylin signaling pathways are simultaneously activated. The ventromedial nucleus of the hypothalamus (VMH) is one site of amylin-leptin interactions. The administration of amylin enhances leptin binding in the VMH, and both leptin and amylin receptor activation initiate some of the same signaling cascades (e.g., STAT3, Akt, and ERK). The STAT3 pathway seems to be particularly important in the interaction between leptin and amylin. Amylin-enhanced leptin signaling in the VMH requires amylin’s induction of interleukin 6 (IL-6). Notably, even following the development of leptin insensitivity (e.g., in obese individuals), amylin administration can restore leptin sensitivity.

The roles of leptin in the development of anorexia and obesity are still controversial

Beyond its effects on energy homeostasis, amylin also seems to exert cognitive enhancing effects, but whether this is achieved through direct interactions in the central nervous system is unclear.

Pramlintide is an amylin agonist approved for the treatment of T1DM and T2DM. Pramlintide is co-administered with insulin analogs and contributes to suppression of postprandial blood glucose by delaying gastric emptying, inhibiting glucagon secretion, and reducing food consumption. Like amylin, pramlintide is primarily deactivated by renal clearance, which also likely involves degradation by insulin-degrading enzyme. In obesity, satiety signals often have a diminished capacity to elicit their anorexigenic effects due to decreased receptor sensitivity. This is particularly true in the case of the adipose tissue-derived satiety signal leptin. In obesity, leptin insensitivity (also called leptin resistance) is profound. However, amylin receptor agonists remain potent appetite-suppressing agents in obese individuals but require continuous administration to effectively treat obesity. Furthermore, in some cases, amylin enhances the anorexigenic effects of other satiety signals (e.g., CCK, PYY, insulin, leptin) when co-administered.

The delay in gastric emptying induced by amylin is most likely achieved through central effects on the dorsal vagal complex of the hindbrain. The dorsal vagal complex contains multiple nuclei and plays a critical role in regulating gastric motility. The dorsal vagal complex includes the area postrema, the nucleus of the solitary tract (NTS), and the dorsal motor nucleus of the vagus nerve (DMV). The area postrema mediates some of the physiological and behavioral effects of amylin, and projects to the NTS. The NTS integrates both neural and endocrine signals (including amylin) and relays the integrated signals to the DMV. The DMB projects preganglionic axons toward the stomach, providing autonomic control over gastric motility. One proposed (though not yet validated) mechanism by which amylin delays gastric emptying is through excitation of the NTS. Amylin may accomplish this excitation of the NTS by interacting with the area postrema to promote the area postrema’s excitation of the NTS (possibly complimenting excitatory glutamatergic vagal input to the NTS) or by directly exciting the NTS. When the NTS is excited by amylin (whether directly or indirectly), the NTS could then modulate the activity of the DMV, resulting in DMV-mediated reductions in gastric motility and delayed gastric emptying. In support of this proposed pathway, gastric emptying is accelerated during hypoglycemia to increase the rate of glucose absorption to raise blood glucose to normal levels. Amylin-activated neurons in the area postrema have been shown to exhibit significant reductions in activity when exposed to low plasma glucose, which, through the same proposed pathway, would yield the increased rate in gastric emptying evident in hypoglycemia. Hypoglycemia may also diminish these neurons’ responsiveness to amylin.

Due to its reliable (albeit reduced) incretin effect, GLP-1 signaling has received more attention than GIP as a viable target for the treatment of T2DM and certain related disorders. By potentiating glucose-dependent insulin secretion, impairing glucose-dependent glucagon secretion, and delaying gastric emptying, exogenous administration of GLP-1 can completely normalize blood glucose in T2DM patients. However, GLP-1 itself is not a practical treatment for T2DM and related disorders because of its short half-life.

In addition to the roles of GLP-1 in regulating energy homeostasis at the level of the hypothalamus, another interesting hypothalamic effect of GLP-1R activation is to promote the secretion of gonadotropin releasing hormone (GnRH) into the hypophyseal portal system, at which point GnRH can stimulate gonadotropin release from the anterior pituitary. This promotion of GnRH secretion is accomplished through an interesting signaling pathway. In GnRH neurons, there is continuous production of 2-arachidonoylglycerol (2-AG, an endocannabinoid) by the enzyme diacylglycerol lipase (DGL) and a tonic retrograde release of 2-AG. The tonic retrograde release of 2-AG inhibits excitatory GABAergic inputs (GABA is usually inhibitory, but GABA is excitatory to GnRH neurons). GLP-1R activation on GnRH neurons increases the production of anandamide (another endocannabinoid). Anandamide in GnRH neurons activates TRPV1 receptors, leading to the inhibition of DGL. This prevents the production and tonic retrograde release of 2-AG. Furthermore, GLP-1R activation also increases the activity of adenylyl cyclase, leading to increased cAMP production, and the consequent activation of protein kinase A (PKA). PKA activates nitric oxide synthase (nNOS), which produces nitric oxide (NO). Nitric oxide is released as a retrograde signal to the excitatory GABAergic inputs, where it promotes GABA release. Thus, GLP-1R activation suppresses 2-AG-mediated inhibition of GABAergic excitation, while also promoting GABAergic excitation through retrograde NO signaling. Both of these effects of GLP-1R activation increase the excitatory GABAergic input to GnRH neurons, resulting in increased excitation of GnRH neurons.

The role of histamine in the stomach explains how antihistamines alter digestive processes: by blocking histamine-mediated excretion of hydrochloric acid.

S

incretins

γ-aminobutyric acid (GABA)

In addition to stimulating pancreatic enzyme and bile excretion, CCK delays gastric emptying, and stimulates the release of somatostatin by δ cells through interactions with the same receptor bound by gastrin. Also like gastrin, CCK release is inhibited by somatostatin, so stimulation of somatostatin release seems to be an autoregulatory mechanism for CCK release. In addition to being inhibited by somatostatin, CCK release is also inhibited by pancreatic polypeptide. Despite the distribution of CCK receptors throughout the brain, circulating CCK is unable to permeate the blood-brain barrier, so it is only able to interact with regions of the hypothalamus and brainstem that lack the protective blood-brain barrier. Circulating CCK promotes satiety through its effects on the hypothalamus and brainstem, and also through stimulation of vagus nerve afferents.

If the chyme entering the duodenum and jejunum contains fat, the presence of fat triggers the release of cholecystokinin (CCK) by I cells. However, CCK is also released by I cells in response to acetylcholine released by the vagus nerve. CCK is both a central neuropeptide and a gastric peptide hormone. In addition to its release by I cells in the duodenum and jejunum, CCK is also released by enteric nervous system neurons as well as by neurons in the brain.

Whereas histamine stimulates parietal cells’ excretion of hydrochloric acid through activation of adenylyl cyclase, somatostatin directly opposes this action; somatostatin receptor activation on parietal cells inhibits adenylyl cyclase. This is a form of negative feedback.

chyme

gastrin also increases the rate of gastric emptying due to the strength of contractions against the pylorus and by relaxing the pyloric sphincter.

An easy solution is to eat a sugar-rich desert following a healthy meal.

gastrin, histamine, and acetylcholine operate synergistically to promote hydrochloric acid excretion. When operating in concert, the effects of gastrin, histamine, and acetylcholine are greater-than-additive

The presence of protein-rich foods accumulating in the lower stomach or stimulation by vagus nerve afferents causes G cells in the pyloric antrum of the stomach to release gastrin, an endocrine signal with numerous targets. Gastrin is also released by enteroendocrine cells in the duodenum in response to large quantities of incompletely digested proteins and it can also be released by the pancreas.

Brown adipose tissue (BAT) has substantial thermogenic capacity; adaptive thermogenesis is the primary function of BAT

White adipose tissue (WAT) lacks thermogenic capacity and primarily serves as a reservoir for energy stored as triglycerides

Iron-pigmented cytochromes

arises

two basic types of adipose tissue