JPC/SMC

ADIPOSE TISSUE
 Adipocytes – individual fat cells (and groups) found throughout loose CT; key role in energy homeostasis
- Also regulate energy metabolism by secreting paracrine and endocrine substances – considered a major
endocrine organ
-  endocrine activity = metabolic and cardiovascular complications associated with obesity
 Stores excess energy (to meet body’s energy demands when nutrient supplies are low) ii. Differentiation
- Body has limited capacity to store carbohydrate and protein, energy reserves stores within lipid droplets in the - Derived from undifferentiated perivascular mesenchymal stem cells associated with adventitia of small venules
form of triglycerides (most concentrated form of energy storage) - Peroxisome proliferator-activated receptor gamma (PPARΥ) in complex with retinoid X factor (RXR) -
- Energy storage (added when food intake > energy expenditure; tapped when energy expenditure > food transcription factors for adipocyte differentiation and initiation of lipid metabolism
intake)  Induces maturation of early lipoblasts (adipoblasts) or preadipocytes into mature fat cells of white adipose
- Energy stored can be rapidly released for use at other sites in body
- Lack water, so they have about twice the energy density of carbohydrates and proteins (37.7 kJ/g) EARLY MIDSTAGE LATE MATURE
- In event of food deprivation, essential source of water and energy  metabolic water obtained from fatty acid - Elongated configuration - Oval configuration - Spherical, increase - Lipid mass
oxidation - Multiple cytoplasmic - Extensive in size compresses nucleus
processes concentration of - Small lipid droplets to an eccentric
I. WHITE ADIPOSE TISSUE (UNILOCULAR) – at least 10% of body weight - Abundant ER and GA vesicles coalesce  single position, signet ring (in
As lipoblastic differentiation - Small lipid droplets large lipid droplet H&E)
i. Functions begins, around nucleus, occupies central - Single lipid droplet
 Forms fatty layer of subcutaneous (superficial) fascia – Panniculus adiposus – in CT beneath skin -  number of vesicles extending toward both portion of
-  rER poles of the cell cytoplasm
 Thermal conductivity of adipose tissue only about half of skeletal muscle
- Small lipid inclusions - Glycogen particles - sER abundant, rER
 Subcutaneous fascia – provides thermal insulation against cold by reducing rate of heat loss
appear at one pole appear at periphery of less prominent
 Found in CT under skin of abdomen, buttocks, axilla, and thigh
- Appearance of pinocytotic lipid droplets
 Sex differences in thickness of this fatty layer – differences of body contour between males and females
vesicles and external - Pinocytotic vesicles
 In both sexes, mammary fat pad is preferential site of accumulation of tissue
lamina (differentiates and basal lamina
 Found in nonlactating female breast; in lactating female, mammary fat pad – support breast function more apparent
adipocytes from proper CT
- Provides lipids and energy for milk production
cells)
- Site for synthesis of different growth factors that modulate responses to different steroid and proteins and
tissue
hormones
 PPARΥ – influence lipogenic pathways and initiate storage of triglycerides
 Preferentially located in greater omentum, mesentery, retroperitoneal space, abundant around kidneys
 PPARΥ/RXR – “master switch” regulator in white adipocytes’ differentiation
 Also found in bone marrow and between other tissues, where it fills in the spaces
- Lipoblasts – initially develop from stromal vascular cells along the small BV in the fetus; free of lipid
 Functions as a cushion in palms of hands and soles of feet, beneath visceral pericardium, orbits around eyeballs
- Committed to become adipocytes by expressing PPARΥ/RXR transcription factors
- Retains structural function even during reduced caloric intake – when adipose tissue elsewhere becomes
- Primitive fat organs – collection of such cells; characterized by proliferating early lipoblasts and proliferating
depleted, remains undiminished
capillaries
 Secretes adipokines – hormones, growth factors, cytokines
- Lipid accumulation – typical morphology of adipocytes
- Tissue is important player in energy homeostasis, adipogenesis, steroid metabolism, angiogenesis,
immune responses iii. Structure
a. Leptin
ADIPOCYTE ADIPOSE TISSUE
- Involved in regulation of energy homeostasis; exclusively secreted by adipocytes
- When isolated, spherical - Delicate meshwork of polygonal profiles
- Inhibits food intake, stimulates metabolic rate and loss of body weight
- When crowded together, polyhedral or oval - Thin strand of meshwork that separates adjacent adipocytes
- Circulating satiety factor – controls food intake when body’s store of energy is sufficient
- Large size – due to accumulated lipid in cell represents cytoplasm of both cells and ECM
- Participates in endocrine signaling pathway – communicates energy state of tissue to brain centers
- Nucleus is flattened, displaced to one side - Richly supplied with blood vessels
that regulate food uptake
of the lipid mass - Capillaries found at angles of meshwork where adjacent
- Acts on CNS by binding to receptors, mainly in hypothalamus
- Cytoplasm forms a thin rim around the lipid adipocytes meet
- Communicates fuel state of adipocytes from fat-storage sites to other metabolically active sites (eg.
- Lipid lost through extraction by organic - Silver stains – adipocytes surrounded by reticular fibers (type
adipose tissue to muscle at a different site)
solvents (xylene) III collagen), which are secreted by adipocytes
- Produces steroid hormones (testosterone, estrogens, glucocorticoids) – not synthesized de novo;
- Special stains – presence of unmyelinated nerve fibers,
converted from inactive forms by specific enzymes in adipocytes, which can influence sex steroid
numerous mast cells
profiles of obese individuals

b. Adiponectin, resistin, retinol binding protein-4, visfatin, apelin, plasminogen activator inhibitor-1, TNFs,
IL-6, angiotensinogen (synthesized in liver;  production = hypertension)
- Obesity-increased secretion of TNF-α, TFG-β, IGF-1, IL-6 and prostaglandins – linked to metabolic
abnormalities and development of diabetes
 Interface between contained lipid and surrounding cytoplasm of adipocyte – composed of condensed layer of
lipid reinforced by parallel vimentin filaments  separates hydrophobic contents of lipid droplets from hydrophilic
cytoplasmic matrix
 Perinuclear cytoplasm – contains small GA, free ribosomes, short profiles of rER, microfilaments, int. filaments;
filamentous forms of mitochondria and multiple profiles of sER also found in the thin rim of cytoplasm
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iv. Regulation
- Interconnected hormonal and neural signals emanating from adipose tissue, alimentart tract, CNS brain-gut-
adipose axis, which regulates appetite, hunger, satiety, and energy homeostasis
2 PHYSIOLOGIC SYSTEMS
SHORT-TERM WEIGHT REGULATION
- Control appetite and metabolism on a daily basis
i. Ghrelin – produced by gastric epithelial cells
- Appetite stimulant
- Acts on anterior lobe of pituitary gland to release
growth hormone
- Functions through receptor located in the
hypothalamus, increasing sense of hunger
- “meal initiator” factor
- Prader-Willi syndrome, overproduction of ghrelin
leads to morbid obesity; compulsive eating and
obsession with food arise at an early age; urge to
eat is physiologic, overwhelming and difficult to
control – if not treated, often die before 30
ii. Peptide YY (PYY) – produced by small intestine
- Appetite suppressant
- Promote and maintain weight loss by inducing
greater sense of fullness soon after a meal
- Acts through receptors in the hypothalamus that
suppress appetite
- Decreases food intake by inducing satiety or a
sense of fullness and desire to stop eating
- Infusion of PYY in humans shown to reduce food
intake by 33% over period of 24 hours
 One of the major metabolic functions: uptake of fatty acids from blood and conversion to triglyceride within
adipocyte (triglyceride stored within cell’s lipid droplet)
 When adipose tissue is stimulated by neural or hormonal mechanism, triglycerides broken down into glycerol and
fatty acids – mobilization
 FA pass through adipocyte cell membrane to enter capillary  bound to carrier protein albumin  transported
to other cells which use fatty acids as metabolic fuel
NEURAL MOBILIZATION
- Important during periods of fasting and exposure to
severe cold
- Adipose cells in denervated fat pad continue to
deposit fat; adipose cells in intact contralateral fat
pad mobilize fat
- Norepinephrine (liberated by nerve endings of
II. BROWN ADIPOSE TISSUE (MULTILOCULAR)
LONG-TERM WEIGHT REGULATION
- Controls appetite and metabolism on a continual basis
(over months and years)
- Leptin and insulin
- Along with, thyroid hormones, glucocorticoids, hormones
of pituitary gland
i. Characteristics
i. Leptin – fat-specific mRNA encoded by leptin (ob) gene
- Mechanism of energy homeostasis
- In obese humans, levels of leptin mRNA in adipose
tissue as well as serum levels are elevated – observed
in all types of obesity (regardless of whether caused by
genetic factors, hypothalamic lesions,  efficiency of
food utilization)
- Adipocytes in obese individuals are resistant to leptin’s
action, administration of leptin doesn’t reduce amount of
adipose tissue
- Individuals who have lost weight and those with
anorexia nervosa – reduced levels of leptin mRNA in
ii. Differentation
adipose tissue and leptin levels in serum
- Protects body against weigh loss in times of food
deprivation
ii. Insulin – pancreatic hormone that regulates blood
glucose levels
- Enhances conversion of glucose into triglycerides of lipid
droplet by the adipocyte
- Regulates weight by acting on brain centers in the
hypothalamus
- In contrast to leptin, required for accumulation of
adipose tissue
iii. Metabolism, Thermogenesis
HORMONAL MOBILIZATION
- Complex system of hormones and enzymes that
control fatty-acid release from adipocytes
- Insulin, thyroid hormones, adrenal steroids
- Insulin – promotes lipid synthesis by stimulating lipid
synthesis enzymes (FA synthase, acetyl-coA
carboxylase) and suppresses lipid degradation by
sympathetic nervous system) – initiates series of inhibiting action of hormone-sensitive lipase, blocking
metabolic steps that lead to activation of lipase – release of FA
splits triglycerides, which constitute >90% of lipids - Glucagon (pancreatic hormone) and growth hormone
stored in adipocyte (early step in mobilization of (pituitary gland) – increase lipolysis (lipid utilization)
lipids) - Elevated levels of TNF-α – causative factor in
development of insulin resistance associated with
obesity and diabetes
 Key thermogenic tissue; present in large amounts in newborn – helps offset the extensive heat loss that results
from the newborn’s high surface-to-mass ratio, and to avoid lethal hypothermia
 In newborns – 5% of total body mass, located on the back, along upper half of the spine, toward the shoulders
 Amount of brown adipose tissue gradually decreases as body grows, but remains widely distributed throughout
first decade of life in cervical, axillary, paravertebral, mediastinal, sternal, abdominal regions
 Disappears from most sites except regions around the kidney, adrenal glands, large vessels (aorta), regions of
the neck (deep cervical and supraclavicular), back (interscapular and paravertebral), and thorax (mediastinum)
 Cells are smaller; cytoplasm of each cell contains many small lipid droplets (“multilocular”)
 Nucleus is typically in an eccentric position within the cells, but not flattened
 H&E – cytoplasm consists largely of empty vacuoles, because lipid in vacuolated spaces is lost during preparation
 Brown adipocytes depleted of their lipid bear close resemblance to epithelial cells than to CT cells
 Contains numerous large spherical mitochondria with numerous cristae, small GA, only small amounts of rER and
sER
 Mitochondria – contains large amounts of cytochrome oxidase – imparts brown color to cells
 Subdivided into lobules by partitions of CT, but CT stroma between individual cells in lobules is sparse
 Rich supply of capillaries (enhances color)
 Numerous unmyelinated, noradrenergic sympathetic nerve fibers present among fat cells
 Derived from mesenchymal stem cells but from a different cellular lineage from white adipocytes
 Brown adipocyte tissue and skeletal muscle derive from common skeletal myogenic progenitor cells – found in
dermatomyotomes of developing emnbryo
 PR domain containing 16 (PRDM16) – zinc finger protein; when activated, myogenic progenitor cells
synthesize several members of PPARΥ coactivator-1 (PGC-1) – acitivate brown adipocyte differentiation and
suppressing skeletal muscle development
 PRDM16/PGC-1 – “master switch” regulator
 Factors regulate expression of genes (UPC-1) that encode a specific mitochondrial protein, uncoupling protein
(UCP-1) or thermogenin (inner mitochondrial membrane protein) – essential for brown adipocyte metabolism
(thermogenesis)
 Under normal conditions, can expand in response to  blood levels of norepinephrine, evident in patients
with pheochromacytoma (endocrine tumor of adrenal medulla secreting excessive amounts of epinephrine
and norepinephrine)  UCP-1 gene is activated by norepinephrine stimulation, protects brown adipocytes by
inhibiting apoptosis
 UCP-2 – linked to hyperinsulinema and obesity, may be involved in regulation of body weight;
 UCP-3 – expressed in skeletal muscles, account for thermogenic effects of thyroid hormone;
 UCP-4 and -5 – brain mitochondrial specific molecules
 Hibernating animals – large amount of brown adipose tissue, serves as ready source of lipid  when
oxidized, produces heat to warm the blood flowing through the brown fat on arousal from hibernation and in
maintenance of body temperature in the cold  nonshivering thermogenesis
 In nonhibernating animals, serves as a source of heat  lipid is mobilized, heat Is generated by brown
adipocytes when they are stimulated by sympathetic nervous system
 Brown adipose tissue can be induced and function in context of human adaptive thermogenesis
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 Mitochondria contains uncoupling protein (UCP-1), which uncouples oxidation of fatty acids from production of
ATP  protons allowed to travel from intermembrane space back to mitochondrial matrix along gradient
without passing through ATP synthase, thus without producing ATP  can occur through UCP-1 that
facilitates proton transport across inner mitochondrial membrane  movement of protons from inner
mitochondrial compartment dissipates mitochondrial proton gradient, uncoupling respiration from ATP
synthesis  thermogenesis (energy produced by mitochondria dissipated as heat)
 Metabolic activity largely contributed by norepinephrine – stimulates lipolysis and hydrolysis of triglycerides;
increases mitochondrial expression and activity of UCP-1 moelcules
 UCP-1 shown to increase during cold stress  stimulates glucose utilization in brown adipocytes by
overexpression of glucose transporters (Glut-4)
 Direct relationship bet. outdoor temp. and amount of brown fat accumulated in body  larger amount of
brown fat in outdoor workers exposed to cold

TRANSDIFFERENTIATION OF ADIPOSE TISSUE

 Exposure to chronic cold temperatures increases thermogenic needs of an organism
 Mature white adipocytes  transform into brown adipocytes to generate body heat
 Brown adipocytes  transform into white adipocytes when energy balance is positive, and body requires an
increase of triglyceride storage capacity
 Changes in phenotype of adipocytes occurs in abnormal cell divisions (no increase in DNA content) or apoptosis
 Mice with abundant natural of induced brown adipose tissue resistant to obesity; genetically modified mice without
functional brown adipocytes are prone to obesity and type 2 diabetes
 Cold exposure and physical activity induce conversion of white-to-brown adipocytes
 Cold temperatures – sensed by CNS, causing increased stimulation of noradrenergic sympathetic nervous system
 Physical exercise – involves secretion of atrial and ventricular natriuretic peptides in the heart that act on the
kidney  activates transcription factors essential for brown adipocyte differentiation
 Other triggers: reprogramming of adipose tissue genes by activating specific transcription factors (“master
regulators”) and growth factors (fibroblast growth factor-21)