Adipose tissue

Characterization and definition

Adipose tissue has distinct morphological and histological characteristics, and executes a
number of activities. In mammals, three types of adipose cells are present: brown, white and
.beige

Brown adipose tissue (BAT), full of mitochondria and specialized in heat production, exerts
its thermogenic function mainly in the first years of life. Posteriorly, it transforms into white
adipose tissue (WAT). However, BAT increased activity has been demonstrated in adults
exposed to low temperatures; interestingly, this thermogenic effect is inversely related to
age – older subjects have diminished expression of uncoupling protein 1 (UCP1) – and
BMI.4,5

Beige adipose tissue, still under investigation, has less well-known functions and it is
believed that it originates from white adipocytes trans-differentiation within the same
cellular lineage (Pax7/myf5-). In animal models, it was demonstrated that these cells,
initially, have a reduced UCP1 expression but, if stimulated, attain the capacity to increase
the activity of these thermogenesis-related proteins. Genetically, they have an intermediate
behavior between brown and white fat tissues; thus, these cells can store the excess of
energy – in form of lipids – in situations where energetic balance is positive, and dissipates
energy to produce heat in cases of thermogenesis stimulation.6

WAT is the most abundant adipose tissue in human organism and is responsible for lipid
storage – in the form of triglycerides, mechanical protection and thermic isolation. However,
interest lies on its capacity of secrete a number of substances with important roles in
cardiovascular risk and protection, the adipokines. There is no consensus about WAT
compartments nomenclature. Based on anatomy and functional properties, Shen et al.
proposed a classification for body fat with emphasis on internal compartments, detected by
image exams (Table 1).7 On the other hand, Foster et al. propose a visual classification,
according to body fat distribution (Fig. 1).8

Subcutaneous white adipose tissue (SAT) has different distribution according to gender. In
men there is increased accumulation in the trunk compared to limbs, with a decreased rate
and a more balanced distribution after the age of 50; in women, accumulation of SAT is
similar in abdomen and limbs until adulthood, when there is an increase of speed and
amount of SAT accumulated in the abdomen.9,10
Visceral adipose tissue (VAT), located between the walls of abdominal cavity, is generally
more prevalent in men than in women. There seems to be a proportional accumulation of
VAT according to total adiposity in men, but not in women, who tend to accumulate fat in
the abdominal cavity after reaching a certain level of total adiposity. Noteworthy is the fact
that women also tend to increase the rate of VAT accumulation after menopause.10

Fat tissue distribution also modifies with aging. In the elderly, while total body fat may
remain stable or even reduced, abdominal SAT is redistributed to VAT. During aging, the
capacity of replication and differentiation of pre-adipocytes in subcutaneous mature
adipocytes during adipogenesis is diminished, creating cells not fully capable of store fatty
acids; thus, these cells can expand to visceral compartments.5,10

Metabolic implications

Adipose tissue is directly controlled by the autonomous nervous system, where sympathetic
fibers relate to catabolic activities (lipolysis) mediated by catecholamines, beta-adrenergic
receptors (β1, 2, 3) and the hormone-sensitive lipase (HSL) enzyme.11 On the other hand,
the parasympathetic fibers modulate anabolic effects in adipocytes (lipogenesis), promoting
insulin-mediated fatty acids uptake.12 It is known, however, that exposure to cold may also
indirectly modulate adipose tissue activity (brown and white) through macrophages
recruitment and interleukin-4 (IL-4) activation, increasing secretion of lipolysis-inducting
catecholamines in WAT and expression of thermogenic genes in BAT.13

Excessive nutrient intake (besides a decrease in energy expenditure) can lead to a number of
responses in different cells (i.e. endothelial, hepatocytes, adipocytes) and cause a series of
metabolic dysfunctions. Specifically regarding endothelial cells, excess of nutrients may
induce inflammation and impair nitric oxide (NO) – a potent vasodilator – production and
release. Similarly, alterations in adipose tissue perfusion can be present.14

In cases of chronic energy imbalance, there is excessive triglyceride accumulation in

adipocytes which is translated in augmented intra-cellular fat content, leading to adipocyte
growth (hypertrophy) and multiplication (hyperplasia). Hypertrophy, especially if
accompanied by vascular supply insufficiency, leads to adipocytes hypoxia and,
consequently, production of reactive oxygen species (ROS); this may cause oxidative stress,
damaging cell structures and triggering an inflammatory response.14,15

Hypertrophied adipocytes are more fragile and susceptible to rupture, even when exposed
to ordinary physical forces; cells in the abdominal cavity are subjected to sudden variations
of intra-abdominal pressure (i.e. during cough and/or exercise). Obese individuals have
elevated intra-abdominal pressure, putting visceral adipocytes under a higher mechanical
stress compared to those in SAT. Macrophage accumulation [major sources of cytokines, like
TNF-α and IL-6, which modulate hepatic production of C-reactive protein (CRP)] in the
adipose tissue occurs mainly around ruptures adipocytes, where inflammatory cells
sequestrate residual lipid droplets. Adipose cells apoptosis starts a cascade of events that
lead to a chronic inflammatory state (low grade inflammation) related to obesity
complications.4,15

Factors that regulate adipocytes hypertrophy and hyperplasia are yet to be completely
clarified; however, insulin and glucocorticoids in high levels seem to stimulate pre-adipocyte
differentiation. Hypertrophied cells increase the production of insulin-like growth factor 1
(IGF1) that also stimulates hyperplasia. Thus, as consequence of a number of different
processes, production of adipokines is impaired in obese persons.14,15

Both subcutaneous and visceral adipose tissues have a differentiated behavior when it
comes to adipokines. In VAT, there is predominance of β1, 2 and 3 adrenergic receptors
compared to α2 ones, which make it extremely sensitive to catecholamine-induced lipolysis
(with consequent increase in free fatty acids release directly into portal circulation). There is
also a minor effect in insulin signaling with a reduction in anti-lipolytic effects, due to a
decrease in insulin receptors substrate 1 (IRS-1). Additionally, there is augmented expression
of 11-Beta hydroxysteroid dehydrogenase type 1 (11β-HSDH1), responsible for conversion of
cortisone into cortisol, enhancing the response to glucocorticoids and, consequently, fat
accumulation. Production of pro-inflammatory adipokines is greater in VAT. SAT, in turn,
fundamentally regulates appetite, energy expenditure and fat deposits through increased
production of leptin. Compared to VAT, lipolysis rates are nearly 50% inferior – gluteo-
femoral compartments of subcutaneous fat have decreased response to catecholamines,
lower density of adrenergic receptors and diminished HSL expression.14,15Table 2 presents
.some adipokines secreted by adipose tissue and their respective functions

White adipose tissue is most abundant in mammals and its distribution greatly varies among
different species.[8] Usually white adipose tissue can be found in two different locations of
the body where it is stored: subcutaneous adipose tissue and intra-abdominal adipose
tissue. Subcutaneous adipose tissue is directly underneath the skin, while the intra-
abdominal adipose tissue surrounds the organs inside the abdomen such as intestine and
kidneys.[8] The intra-abdominal adipose tissues covers the thoracic and abdominal cavity.
The visceral adipose tissue is part of the intra-abdominal adipose tissue that surrounds the
intestine for the most part.[8] White adipose tissue exists mostly as a single adipocytes in
the subcutaneous tissue.[9]

Role of Mitochondria in Adipose Tissues Metabolism and Plasticity

White Adipose Tissue

WAT is considered to be the main energy store of the organism and a high-endocrine organ,
secreting numerous adipokines including leptin and adiponectin,12 and therefore affects the
function of several tissues in the body. Such activities are supported mainly by mature white
adipocytes that exhibit a large unilocular lipid droplet, nucleus, and mitochondria being
pushed near the plasma membrane.3 WAT is distributed into different fat pads that can be
classified either as subcutaneous or visceral depots and that display specific biological
functions. Subcutaneous WAT generally is viewed as a protective tissue, whereas visceral
WAT is associated with an adverse metabolic profile, probably because it drains free fatty
acids directly into the liver through the portal vein and because higher release of adipokines
such as the interleukin-8 or the plasminogen activating factor.13, 14 Whether the two
.depots have different mitochondrial content is not clear

Although the subcutaneous inguinal fat pad of rats has been shown to contain less
mitochondria than the visceral one,15 decreased mitochondrial content associated with high
oxidative stress has been shown in visceral fat pad of C57Bl6 mice and could account for
mechanisms mediating the elevated metabolic risk associated with this fat depot.16 WAT
ensures healthy storage of excess nutrients during positive energetic balance and rapid
energy mobilization through fatty acids release to supply other organs in case of metabolic
needs. WAT has a great ability to store surplus energy in the form of lipids and to expand
because of apparent adipocyte hyperplasia, which corresponds to an increase in the number
of adipocytes because of the proliferation and differentiation of adipose progenitors, and
hypertrophia that corresponds to enlargement of existing adipocytes (by de novo lipogenesis
or fatty acids uptake from the circulation).17 In the case of sustained energy overload and
obesity, however, WAT undergoes fibro-inflammation and becomes dysfunctional, reaches
its expandability limits, leading to insulin resistance, ectopic lipids accumulation, and
dysfunction of organs, including liver and muscle.18 This WAT alteration contributes to
increase risks of cardiovascular diseases and type 2diabetes.8 Mitochondrial dysfunctions
within adipose cells might be involved in such adipose tissue dysfunction, as developed in
.paragraphs 4.2

WHITE ADIPOSE TISSUE

BROWN ADIPOSE TISSUE

Interscapular

Paravertebral •

BEIGE ADIPOSE TISSUE

Localization
Subcutaneous •

Intra-abdominal •

Epicardial⚫

Gonadal •

Perirenal • Cervical •

Supraclavicular

Morphology

Spherical

Elliptical and smaller than white

Emerges in white adipose tissue depots with appropriate stimuli

Spherical

Unilocular morphology but small lipid droplets after stimulation • Mitochondria appear •
after stimulation

Cell composition

Single lipid droplet ⚫

Few mitochondria •

Flattened peripheral nucleus •

Little endoplasmic reticulum

Multiple small lipid droplets •

Large number of mitochondria •

Oval central nucleus •

Function

Storing energy

Uncoupling protein

Undetectable

Expending energy and heat production (non- shivering thermogenesis)

Thermogenic potential

Positive
Positive after stimulation

The muscularis externa is responsible for segmental contractions and peristaltic movement
in the GI tract. These muscles cause food to move and churn together with

There are usually two layers; the inner layer is circular, and the outer layer is longitudinal.
These layers of smooth muscle are used for peristalsis (rhythmic waves of contraction), to
.move food down through the gut

The digestive system is endowed with its own, local nervous system, referred to as the
enteric nervous system (ENS). Given the varied functions of small intestine, its ENS has
developed individualized characteristics relating to motility, secretion, digestion, and
inflammation. The ENS regulates the major enteric processes such as immune response,
detecting nutrients, motility, microvascular circulation, intestinal barrier function, and
epithelial secretion of fluids, ions, and bioactive peptides. Remarkable progress has been
made in understanding the signaling pathways in this complex system and how they work. In
this article, we focus on recent advances that have led to new insights into small intestinal
.ENS function and the development of new therapies

The nervous system of the small intestine is made up of the parasympathetic and
sympathetic divisions of the autonomic nervous system. The parasympathetic fibers
originate from the Vagus nerve and control secretions and motility
?Is the small intestine a skeletal muscle

In the mouth and pharynx, it consists of skeletal muscle that aids in swallowing. In the rest of
the digestive tract, it consists of smooth muscle (three layers in the stomach, two layers in
the small and large intestines) and associated nerve fibers

?Is there skeletal muscle in the intestine

In the human gastrointestinal tract, the muscles in the proximal two-thirds of the
oesophagus and in the external anal sphincter are skeletal; the rest of the tunica muscularis
contains smooth muscle cells (SMCs).1