Oversikt, Endokrine Prinsipper
Jan O. Gordeladze
j.o.gordeladze@medisin.uio.no
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Definisjon av «endokrinologi»
“Endocrinology: The study of the
medical aspects of hormones,
including diseases and conditions
associated with hormonal imbalance,
damage to the glands that make
hormones, or the use of synthetic or
natural hormonal drugs.
An endocrinologist is a physician who
specializes in the management of
hormone conditions”.
Noen kjente hormoner
(peptider, aminosyrer/ASderivater og steroider er
nevnt til venstre, mens
såkalt enkelt tilbakekobling
(«feedback» og såkalt
hierarkisk («nivåbasert»)
hormonell kontroll er
skissert til høyre:
Repetisjon av signalveier ved hjelp av en
data-basert TBL-sesjon (enkel variant med
«true or false» utsagn
se lenke:
Team-basert læringsmodul 2:
«Moderne» måte å vurdere kommunikasjon mellom organsystemer:
Ikke bare såkalt «hierarkisk», men også «multi-sideways»: «Organ Cross-Talk»
“The communication between tissues of the human body is mediated via a great variety of biological active proteins, the so called
kines. These kines are released in a tissue specific manner constituting the organ secretomes. They exert endocrine, autocrine
and paracrine functions. Alterations of those kine profiles may play a pivotal role in the pathogenesis of multifactorial diseases.
Although many attempts have been made to elucidate tissue specific secretomes, their complex nature still remains incompletely
characterized. The communication network between the different tissues and involvement and special function of the “kines”
define a novel pathophysiological concept of the organ crosstalk”.
Hvilke hormoner snakker vi om og hvilke organer gjelder for
denne måten å tilnærme seg endokrinologien på?
Organs «cross-talking» to regulate blood insulin levels: Hypothalamus, Liver,
white fat tissue (WAT), muscle, bone, ovary, GI-tract, pituitary, and placenta
Pancreatic β cells are critical to glucose homeostasis in the fed state, as they release insulin into the circulation, which
stimulates glucose metabolism in liver, muscle, white adipose tissue and insulin action in brain cells. Other organs also
modulate β-cell mass and function via secreted hormones that act on β-cell receptors to adapt to physiological changes or
metabolic stresses. Abbreviations: E2, 17β-oestradiol; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1;
PL, placental lactogen; WAT, white adipose tissue..
Skeletel muscle as an endocrine organ, «reciprocally» involved in regulating
the function of WAT, bone, pancreas, blood vessels and liver
LIF, IL-4, IL-6, IL-7 and IL-15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy and exercise
provokes the release of a myostatin inhibitor, follistatin, from the liver. BDNF and IL-6 are involved in AMPKmediated fat oxidation and IL-6 enhances insulin-stimulated glucose uptake. IL-6 appears to have systemic effects
on the liver and adipose tissue and increases insulin secretion via upregulation of GLP-1. IGF-1 and FGF-2 are
involved in bone formation, and follistatin-related protein 1 improves endothelial function and revascularization
of ischaemic vessels. Irisin has a role in 'browning' of white adipose tissue.
Hvordan SCFA («kort-kjedete fettsyrer») som dannes i tykktarmen er involvert
i reguleringen av: funksjoner i lever (insulinfølsomhet og fettakkumulering), WAT
(lipolyse, betennelser), muskelfunksjon, (insulinfølsomhet, lipidnivå) og
sentralnervøs metthetsfølelse
Fermentation of indigestible foods in the distal
intestine results in the production of SCFA. The
ratio of acetate to propionate to butyrate in the
ileum, caecum and colon is ~3:1:1. Butyrate and
propionate are generally metabolized in the colon
and liver and, therefore, mainly affect local gut
and liver function. In the distal gut, SCFA bind to
GPR41 and GPR43, which leads to the production
of the gut hormones PYY and GLP-1 and affects
satiety and glucose homeostasis. Furthermore,
propionate and butyrate might induce intestinal
gluconeogenesis and sympathetic activity,
thereby improving glucose and energy
homeostasis. Small amounts of propionate and
butyrate and high amounts of acetate reach the
circulation and can also directly affect peripheral
adipose tissue, liver and muscle substrate
metabolism and function. In addition, circulating
acetate might be taken up by the brain and
regulate satiety via a central homeostatic
mechanism. Whether metabolic effects are
mainly explained by direct effects of SCFA or
indirectly via gut-derived signaling molecules still
remain unclear. Solid lines indicate direct SCFA
effects and dashed lines indicate indirect SCFA
effects.
Abbreviations:
AMPK,
adenosine
monophosphate-activated protein kinase; FA,
fatty acid; GLP-1, glucagon-like peptide-1; GPR, Gprotein coupled receptor; PYY, peptide YY; SCFA,
short-chain fatty acid.
Influence of WAT
(white adipose tissue)
on the homeostasis of
skeletal muscle,
pancreas, and liver
Under conditions of positive energy balance (that is, energy intake is much greater than energy expenditure), adipose tissue
exceeds its buffering capacity to store all excess energy in the form of TG, which results in overflow of lipids into the circulation.
This increased lipid supply to nonadipose tissues such as the liver, skeletal muscle and pancreas results in ectopic fat storage in
these tissues and the development of insulin resistance. Together with a reduced lipid buffering capacity, adipose tissue becomes
inflamed, which results in an increased production and secretion of proinflammatory cytokines and adipokines, such as tumour
necrosis factor (TNFα), IL-6 and C-C motif chemokine 2 (commonly known as monocyte chemoattractant protein-1), which might
also contribute to the development of peripheral insulin resistance and a disturbed glucose homeostasis. Abbreviations: FA, fatty
acid; TG, triglyceride.
The regulatory loops triggered by «hedonic inputs», like eating a
veloptuous piece of cace (or just thinking about ?)
The brain integrates long-term energy
balance. Peripheral signals relating to longterm energy stores are produced by adipose
tissue (leptin) and the pancreas (insulin).
Feedback relating to recent nutritional state
takes the form of absorbed nutrients,
neuronal signals, and gut peptides. Neuronal
pathways, primarily by way of the vagus
nerve, relate information about stomach
distention and chemical and hormonal milieu
in the upper small bowel to the NTS within
the dorsal vagal complex (DVC). Hormones
released by the gut have incretin-, hunger-,
and satiety-stimulating actions. The incretin
hormones GLP-1, GIP, and potentially OXM
improve the response of the endocrine
pancreas to absorbed nutrients. GLP-1 and
OXM also reduce food intake. Ghrelin is
released by the stomach and stimulates
appetite. Gut hormones stimulating satiety
include CCK released from the gut to
feedback by way of vagus nerves. OXM and
PYY are released from the lower
gastrointestinal tract and PP is released from
the islets of Langerhans.
Environmental impact on energy metabolism
Exposure to low
ambient
temperature will reduce the
impact of
the negative
feedback of T4 on the anterior
pituitary, thus enhancing the
metabolism
or
energy
production in general.
Also mentionable is that cold
exposure to skin surfaces over
brown adipose tissue will
activate the body’s fatty acid
metabolism, producing but
heat, thus reducing the body
stores of
«detrimental»
triglycerides.
Interaction between tumour tissue and
skeletesl muscle and liver, respectively
During tumour growth, substantial metabolic
alterations take place in cancer patients. Thus,
protein degradation is stimulated in skeletal
muscle, which results in a massive amino acid
efflux to the circulation. Therefore, a flow of
nitrogen (mainly in the form of alanine) from
skeletal muscle reaches the liver, where this
amino acid is used to sustain gluconeogenesis
and also the synthesis of acute-phase proteins.
Glutamine is also exported from the muscle and
used mainly in the tumour as a nitrogen donor
for the synthesis of both protein and DNA. The
tumour, depending on the availability of
glucose, can also oxidize some glutamine.
Adipose tissue mass is reduced owing to the
activation of lipases, which participate in the
lipolytic breakdown of triacylglycerols (TAGs),
which produces both non-essential fatty acids
(NEFAs) and glycerol. Glycerol can also be used
to sustain liver gluconeogenesis while the NEFAs
are used by the tumour mass, albeit at very low
levels. Instead, tumour cells use huge amounts
of glucose and thereby generate lactate, which
is then exported to the circulation. The liver also
uses lactate as a gluconeogenic substrate, partly
to compensate for the acidosis associated with
lactate production. The recycling of lactate
constitutes a 'Cori cycle' (shown in purple)
between the liver and the tumour, which is
linked with high energetic inefficiency, as the
conversion of glucose into lactate by the tumour
generates much less ATP than the amount
required to produce glucose from lactate.
Circled “+” symbols indicate pathways that are
activated during cachexia.
Cancer cells «urge» white adipose tissue (WAT) to become brown adipose
tissue (BAT), leading to cachexia («avmagring, kraftløshet»)
In addition to massive lipolysis,
decreased lipogenesis from glucose
and impaired entry of fatty acids
owing to decreased activity of
lipoprotein lipase (LPL) contribute
to adipose tissue wasting. In
addition, very recent data suggest
that, during cancer cachexia, white
adipose cells acquire some of the
molecular
machinery
that
characterizes brown adipose cells.
This represents a 'browning' of
white cells, in which uncoupling
protein 1 (UCP1) is expressed and
promotes
uncoupling
and,
consequently, heat production and
energetic inefficiency. This cell
conversion can be triggered by
both
humoral
inflammatory
mediators, such as interleukin-6 (IL6), and tumour-derived compounds, such as parathyroidhormone-related protein (PTHRP).
Circled “+” symbols indicate
pathways that are activated during
cachexia. Dashed arrows indicate
pathways that are suppressed. LMF,
lipid mobilizing factor; Pi, inorganic
phosphate.
Other organs
affected by
cancer cachexia
Phenomenon
applicable to
caloric
restriction
(anorexia) or
extreme
eurexia!
In addition to skeletal muscle and adipose tissue, other organs are affected by the cachectic process. In fact, the wasting that
takes place in muscle could well be dependent on alterations in other organs or tissues, such as white adipose tissue (see the
main text). Abnormalities in heart function, alterations in liver protein synthesis, changes in hypothalamic mediators and
activation of brown adipose tissue are also involved in the cachectic syndrome.
Integrated
metabolic signals
(emanating from
perifer organs) in
the central
nervous system
(CNS)
Schematic presentation of intertissue
communication (quoted with slight
modification from Yamada & Katagiri,
2007). The brain receives various
forms of metabolic information from
peripheral organs/tissues through
humoral and neuronal pathways.
These inputs are probably integrated
and processed in the brain, leading to
appropriate systemic responses.
Several signals, as therapeutic targets,
are discussed in this article.
Interaction between the parathryroid gland, kidney, and bone tissue in
the regulation of blood calcium levels
Parathyroid hormone
(PTH)
stimulates the production of
active vitamin D (1,25D) in the
kidney. 1,25D enhances the
uptake of Ca from the intestine.
PTH
also
facilitates
the
breakdown of bone tisse in order
to rerlease Ca to the circulation.
The secretion of PTH is
subjected to negative feedback
from both serum 1,25D and Ca.
FGF23 is released from bone
(osteocytes) and functions as an
inhibitor of the production of
1,25D (active vitamin D) in the
kidney and the secretion of PTH
from the parathyroid gland.
During grave kidney failure
(uremia), the regulatory loops
are «broken», and PTH secretion
is chronically elevated, leading
to loss of Ca from the bone and
deposition in soft tissues like
heart valves and arteries.
The effect
of light on
various
biological
and
behavioural
phenomena
Diurnal variation
of physiological/
bodily phenomena
Diurnal variation of some hormones/hormonal regulatory loops with inpact
(i.e. adaptible function) on tissue related/bodily fuctions
Abbreviations: F, female
individuals only; FGF21,
fibroblast growth factor 21;
GH, growth hormone;
M, male individuals only;
RAAS, renin–angiotensin–
aldosterone system.
Integrative role for the circadian clock in the regulation of
physiological function
Circadian proteins listed in parentheses dictate which proteins have been implicated in regulating the process in
question. If a protein is not listed, it does not imply that it is not involved, but that it has not yet been tested. Green
arrows represent induction by the circadian protein; red arrows represent repression. The time shown on the clock is for
illustrative purposes only.
The diurnal variation of key genes determining bodily functions is
regulated by CLOCK and PER (period) genes
Glucose transporters are
subject to diurnal variation!
SGLT1
Patients with IBS («irritable bowel
syndrome» will probably benefit
from ingesting sugar-containing
foodstuff later in the day!
Or stick to a diet low in FODMAPs!