Hormonal control of metabolism

By: Cristhian Camilo Lozano Fernández

Abstract

Cells of the body require nutrients in order to function, and these nutrients are obtained
through feeding. In order to manage nutrient intake, storing excess intake and utilizing
reserves when necessary, the body possess an extraordinary and, at the same time, complex
machinery that is responsible for doing so, this machinery is made up of hundreds of peptides
released primarily from the pancreas, liver, intestines, brain, muscle and adipose tissue,
besides there is an extend network of neurons that regulates this functions.

At the organic level, hunger and satiety is directed by the hypothalamus results from the
production of neuropeptides that stimulate organs like the pancreas, intestine and adipose
tissue, which in turn produce hormones; among the most important, insulin and glucagon
which generate the activation and inactivation of the enzymes that regulate metabolic
pathways in the cells.

In this abstract I am going to present a review of the major hormones and some of the main
cerebral areas involved in metabolism regulation

Regulation at CNS

The hypothalamus constitutes less than 1% of the total mass of the human brain and is the
main control center of the energy balance of human body. The hypothalamus participates in
regulation of a variety of functions like the temperature, food intake, thirst, hormonal balance,
reproduction and circadian rhythms. Among the nuclei that comprise the hypothalamus, the
arcuate nucleus (ARC) is one of the major mediators in the regulation of food intake, its
position is adjacent to the median eminence, allowing the ARC to sense circulating signals such
as leptin, ghrelin and insulin, amongst others. Through changes in the activity of its neuronal
populations and through many diverse and widespread outputs, the ARC is a major participant
in the regulation of energy metabolism (1).

Among the most important neurotransmitters involved in the production of hungry and satiety
are the neuropeptide Y (NPY) that in addition with the aguti-related protein (AgRP), are the
main orexigenic neuropeptides.

The most abundant is NPY it belongs to the polypeptide family pancreatic (PP), activates a
large amount of orexigenic and anorectic neurons; in the adipose tissue decreases the
expression of lipogenic enzymes, increases the accumulation of fat and reduces energy
expenditure. On the other hand, the increase of leptin and cholecystokinin, stimulates the
anorexigenic neurons of the NArq and they stimulate the production of melanocortins,
peptides derivatives of the molecule pro-opiomelanocortin (POMC), which inhibits appetite
and increases the sympathetic nervous system activity, basal insulin secretion is reduced and
this lead to the control of body weight

The release of GABA from AgRP neurons can be dynamically regulated. Fasting causes
increased GABA release, whereas leptin decreases GABA release from AgRP neurons onto
POMC neurons. The importance of the ARC as a mediator of the orexigenic action of ghrelin
emerges from the fact that the absence of AgRP/NPY neurons eliminates the ghrelin-triggered
increase in food intake. The AgRP/NPY neurons send projections to other hypothalamic nuclei
such as the paraventricular nucleus (PVN), the dorsomedial nucleus of the hypothalamus
(DMH) and the lateral hypothalamic area (LHA) which are all involved in the control of feeding.

In special metabolism states such as pregnancy or lactation there is an increase of certain brain
areas resulting in the release of the hormone prolactin that is supposed to be a factor
mediating hyperphagia, probably sustained by leptin-resistant hypothalamic centers
controlling food intake. The presence of PRLR in brain areas associated with the regulation of
energy balance and food intake, as well as in white and brown adipose tissue, liver and
pancreas, raises the possibility that prolactin is involved in the regulation of energy balance
acting at different levels. Increased food intake, together with prolactin acting at different
organs, modifies energy metabolism. There is an increase in adiposity, higher serum non-
esterified fatty acids and triglycerides. At the pancreatic level, the insulin response to glucose is
impaired, which results in glucose intolerance, high serum glucose and hyperinsulinaemia.
Altered glucose metabolism may be responsible for the increased lipid content in the liver.
These results highlight the role of prolactin as a metabolic hormone acting on different organs
to reinforce its role during pregnancy, which is to store energy for future demands.

At peripheral level

There is a group of hormones involved in metabolism regulation that are produced in different
organs in human body, this hormones interacts with several areas in brain but, as mentioned
above the hypothalamus is the more related to energy balance and then in regulating
metabolism:

Ghrelin

Ghrelin is a 28-amino acid peptide secreted by cells located within the gastrointestinal tract
are found mainly in the stomach and duodenum, but also in the jejunum, lungs, pancreatic
islets, gonads, adrenal cortex, placenta, and kidney. It has also been shown that ghrelin is
produced locally in the brain. It was first discovered as the endogenous ligand of the growth
hormone secretagogue receptor 1a (GHSR1a), with the ability to stimulate the secretion of
growth hormone from the anterior pituitary gland. The ghrelin receptor GHS-R1a (a splice-
variant of the growth hormone secretagogue receptor, with the GHS-R1b splice being inactive)
is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of
growth hormone release, increase in hunger, modulation of glucose and lipid metabolism,
regulation of gastrointestinal motility and secretion, protection of neuronal and cardiovascular
cells, and regulation of immune function. They are present in high density in the hypothalamus
and pituitary, on the vagus nerve (on both afferent cell bodies and efferent nerve endings) and
throughout the gastrointestinal tract Ghrelin acts on the CNS by binding to GHSR1a, which is a
G protein coupled receptor highly expressed in brain centers associated with food intake. The
main neuronal targets that mediate the orexigenic action of ghrelin are the ARC of the
hypothalamus and the dorsal vagal complex (DVC) of the brainstem.

The DVC is another important brain area that mediates the orexigenic action of ghrelin. This
brain region is made up of three nuclei: the nucleus of the solitary tract, the area postrema
and the dorsal motor nucleus of the vagus. The expression of GHSR1a mRNA has been
described in all three components of the DVC , suggesting that ghrelin can directly act on
them. Indeed, it has been shown that the administration of ghrelin directly on the DVC
promotes food intake. Considering that ghrelin is the only peptide hormone known to increase
food intake, its relevance in the regulation of energy homeostasis is highlighted. Although the
brain targets for the orexigenic action of ghrelin are well established, the exact molecular
mechanisms by which this hormone regulates feeding are not completely understood.
Unravelling these mechanisms is of extreme importance with respect to considering them as
potential therapeutic targets in the treatment of pathologies that affect food intake.

Oxysterols

The oxysterols are involved in different mechanisms related to the removal of cholesterol from
cells. These compounds are capable of binding to specific proteins called LXRs acting as their
endogenous ligands. The functional LXRs exist as two isoforms: LXRa and LXRb. The first is
mainly expressed in the liver and, to a lesser extent in the gut, adipose tissue, kidney, spleen
and macrophages, whereas LXRb is expressed in almost all tissues. Upon exposure to excessive
accumulation of intracellular cholesterol oxides, LXRs activate a programme of gene expression
for limiting the pathogenic accumulation of cholesterol. In the intestine, activation of LXRs
decreases cholesterol absorption from the diet by promoting the expression of excretion
transporters such as ABCA1, ABCG5 and ABCG8 (45). In macrophages, LXRs cause a rapid
increase in the expression of genes involved in the formation of high-density lipoprotein and
reverse cholesterol transport.

Insulin

Is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the
main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and
protein by promoting the absorption of glucose from the blood into liver, fat and skeletal
muscle cells. In these tissues the absorbed glucose is converted into either glycogen via
glycogenesis or fats (triglycerides) via lypogenesis, or, in the case of the liver, into both.
Glucose production and secretion by the liver is strongly inhibited by high concentrations of
insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of
tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in
the blood into large molecules inside the cells. Low insulin levels in the blood have the
opposite effect by promoting widespread catabolism, especially of reserve body fat.

After of food intake, there is an induction of insulin releasing and this is done by three
mechanisms. First, stimulates the entry of glucose to peripheral tissues such as skeletal muscle
and adipose tissue by the transfer of the glucose transporters to the cell membrane. Second,
promotes the storage of glucose in the form of glycogen in the liver and third, Inhibits
glucagon secretion from pancreatic α cells, thus preventing hepatic glucose production. In
addition, insulin stimulates fat synthesis, promotes the storage of triacylglycerol in adipose
cells, and promotes protein synthesis in the liver and skeletal muscle.

Insulin is stored in large core-dense vesicles within the b-cells Increased intracellular Ca++
levels are detected by a family of sensorproteins, synaptotagmins, which in turn form a
complex with synaptosomal-associated receptor proteins (SNAREs) to trigger the fusion of the
insulin vesicles with the plasma membrane and the release of the hormone into the
extracellular environment through exocytosis. Following glucose stimulation, the insulin
precursor proinsulin is cleaved to form equal amounts of insulin and connecting peptide (C-
peptide). Insulin release from b-cells is biphasic, with a major peak within the first 5 minutes of
a glucose stimulus follow by a slower smaller peak.(2)
Glucagon

Accurate glycemic control by the islets is very much dependent on the opposing arm of the
regulation involving a second hormone glucagon. In contrast to insulin, glucagon release by a
cells of the pancreatic islets is triggered by a reduction in blood glucose levels. Glucagon
opposes hypoglycemia by mobilizing glucose into the plasma through increased glycogenolysis
and gluconeogenesis. In addition, the simultaneous inhibition of the intra-hepatic glycolysis
and glycogenesis impedes further glucose uptake by hepatocytes. The islet centered model for
glycemic control proposes that the regulatory process is initiated primarily by the effect of high
levels of blood glucose.

Figure 1 shows a schematic view of the glucose balance or imbalance occurred in body and the
influence of insulin and glucagon.

Figure 1 schematic representation of the glucagon-insulin and glucose homeostasis, taken from
https://doi.org/10.1016/j.mpaic.2007.04.009

Incretins

Insulin secretion is favored by the secretion of intestinal hormones called incretins ("Incretine:
INtestine seCRETtion Insulin"), which are the hormones responsible for a greater response to
glucose administered orally, compared to intravenous. Incretins are synthesized and released
by the gastrointestinal tract.(3)

Incretins activate neural circuits that communicate with peripheral organs including the liver,
skeletal muscle, adipose tissue, and the pancreas, thus regulating the intake and assimilation
of glucose.
Within the group of incretins are glucagon-like peptide (GLP-1) and gastric inhibitory
polypeptide (GIP), which are secreted by the L and K cells of the intestinal wall, respectively, in
response to the presence of food. . These peptides exert their effect by their specific binding to
their respective GPI-R and GLP1-R receptors, which belong to the family of G-protein coupled
receptor

Leptin

Is a hormone predominantly made by adipose cells and enterocytes in the small intestine that
helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in
adipocytes. Leptin acts on cell receptors in the arcuate and ventromedial nuclei, as well as
other parts of the hypothalamus and dopaminergic neurons of the ventral tegmental area,
consequently mediating feeding.

In obesity, a decreased sensitivity to leptin occurs (similar to insulin resistance in type 2

diabetes), resulting in an inability to detect satiety despite high energy stores and high levels of
leptin.

Leptin acts directly on leptin receptors in the cell membrane of different types of cells in the
human body in particular, and in vertebrates in general. The leptin receptor is found on a wide
range of cell types. It is a single-transmembrane-domain type I cytokine receptor, a special
class of cytokine receptors. Further, leptin interacts with other hormones and energy
regulators, indirectly mediating the effects of: insulin, glucagon, insulin-like growth factor,
growth hormone, glucocorticoids, cytokines, and metabolites.

The primary function of the hormone leptin is the regulation of adipose tissue mass through
central hypothalamus mediated effects on hunger, food energy use, physical exercise and
energy balance. Outside the brain, in the periphery of the body, leptin's secondary functions
are: modulation of energy expenditure, modulation between fetal and maternal metabolism,
and that of a permissive factor in puberty, activator of immune cells, activator of beta islet
cells, and growth factor.

In humans, many instances are seen where leptin dissociates from the strict role of
communicating nutritional status between body and brain and no longer correlates with body
fat levels:

- Leptin plays a critical role in the adaptive response to starvation.(4)

- Leptin level is decreased after short-term fasting (24–72 hours), even when changes in
fat mass are not observed.(5)
- Serum level of leptin is reduced by sleep deprivation.(6)
- Leptin levels are paradoxically increased in obesity. (7)
- Leptin level is increased by emotional stress.(8)
- Leptin level is chronically reduced by physical exercise training. (9)
- Leptin level is decreased by increases in testosterone levels and increased by increases
in estrogen levels. (10)
- Leptin level is increased by insulin.(11)
- Leptin release is increased by dexamethasone. (12)
- In obese patients with obstructive sleep apnea, leptin level is increased, but decreased
after the administration of continuous positive airway pressure (13). In non-obese
individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase
leptin to normal levels.
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