CELL 305 -- lesson 16 -- adipose physiology

What is the trend for adipocyte development over our lifespan?

- Increase in adipocyte number and size until end of adolescence

- then both level out through adulthood

- finally, at the end of our lives, hyperplasia decreases and hypertrophy increases

Where do you find brown fat and what are its main functions?

1. Typically sprinkled through thoracic cavity

2. Primary job is to produce heat

Where do you find SubQ fat and what are its main functions?

1. all the fat stored beneath the skin that we can pinch and jiggle around our entire body (most abundant form of fat)

2. Involved in Energy storage (calories) and insulation (keeps us warm)

Where do you find visceral fat and what are its main functions?

1. Deep within belly surrounding tissues

2. Energy storage, immunity, and organ protection (shock absorption to internal, visceral organs)

* Most vilified area of fat

How does our body store fat? Walk through the process

1.Insulin binds to its receptor

2.Signaling cascade goes through AKT and TSC complex and activates mTOR

3.mTOR binds to SREPB-1C

4.SREPB-1C induces gene transcription from nucleus and activates creation of all the enzymes used for lipogenesis

What is the difference between LPL and all those other enzymes (ACC, FAS, DGAT, GPAT) stimulated by SREPB-1C?

LPL delivers fatty acids to tissues where they can be used for energy (muscle) or storage (adipose).

Lipogenic enzymes synthesize new fatty acids and triglycerides inside cells, contributing to fat storage when there’s excess energy.

LPL:

Releases fatty acids from triglycerides carried in the blood.

Fatty acids can either be used for energy or stored as triglycerides.

Other Enzymes:

Take excess fatty acids (released by LPL or synthesized de novo from glucose) and reassemble them into triglycerides for long-term storage.

This system ensures the body maintains a balance between immediate energy availability and long-term energy reserves, depending on its current needs.

LPL is like a grocery delivery service that brings ready-to-use ingredients (fatty acids) to your house (fat cells).

SREBP-1c-stimulated enzymes are like a chef in your kitchen, making those ingredients from scratch (lipogenesis).

What is the difference between lipogenesis and adipogenesis?

- adipogenesis is the formation of mature adipocytes from precursor cells, preadipocytes

- making new adipocytes (hyperplasia)

- lipogenesis is the synthesis (building up) of fatty acids and triglycerides which are then stored in adipocytes.

- fat cell increasing its own fat supply thus making it bigger (hypertrophic)

Adipogenesis is about creating and maintaining the fat cells (adipocytes) themselves.

Lipogenesis is about synthesizing and storing triglycerides within these fat cells.

How do fats travel through the blood? What enzyme helps us store those fats? What do we store them as? Walk through the process

1.The majority of the fat traveling through our blood (that can be stored) is being transported on Triglyceride-rich lipoproteins

- This includes things like chylomicron (from when you eat fat) and triglyceride rich lipoproteins made from liver like VLDL and LDL

2.When the TRLs bump into LPL, the LPL will start pulling those fatty acids off the triglyceride

3.LPL will then reform those fatty acids into a triglyceride for storage

- re-esterification via GPAT, DGAT, etc.

lipogenesis

* Lipoprotein lipase is incredibly important for fat storage

* LPL takes fat from the blood (FFA) and recreates that into a triglyceride to be stored

* If insulin is up, free fatty acids are down (because insulin is telling LPL to convert them into triglycerides to be stored)

What is the personal fat threshold?

The personal fat threshold is how much fat can be stored in cells

- more cells = higher fat carrying capacity

- less cells = lower fat carrying capacity

What happens when you store more fat than your threshold can handle?

If person has fat cells filled below threshold:

They are metabolically healthy and are insulin sensitive

If person stores more fat than their threshold (what fat cells can handle):

They are not metabolically healthy and are insulin resistant

* Insulin resistance versus insulin sensitivity showcases metabolic health

^ this is largely determined by the size of the fat cell

What is liposuction?

Where are we taking that fat from?

Are we taking hypertrophic or hyperplastic cells? Why does that matter?

How will this affect your personal fat threshold and your insulin resistance?

liposuction is sucking the fat cells out, not shrinking them

we are taking away subcutaneous fat

We are reducing the NUMBER of fat cells, not the SIZE of the fat cells. This lowers your personal fat threshold and has no healthy impact on our insulin levels or insulin resistance

Not helpful because size of fat cells matters more than total amount of fat cells

No change in health

What is hypertrophy?

increase in cell size

what is hyperplasia?

increase in number of cells

what is lipogenesis?

This term refers to the process of converting acetyl-CoA or glucose into fatty acids for storage.

- fat cell increasing its own fat supply thus making it bigger (hypertrophic)

what is adipogenesis?

The process by which adipocytes develop and accumulate

- making new adipocytes (hyperplasia)

adipose growth occurs through what 2 mechanisms

hypertrophy (lipogenesis) and hyperplasia (adipogenesis)

You cannot understand the growing or shrinking of fat tissue without understanding...

insulin --> hypertrophy and hyperplasia are only possible with elevated insulin

which cellular signal mediates hypertrophy

If a fat cell is going under hypertrophy, its because intracellular protein, SREBP-1 C has been activated

which cellular signal mediates hyperplasia

If a fat cell is going under hyperplasia, it's because PPAR-gamma is activated

lipogenesis versus lipolysis

lipogenesis = Lipogenesis is the biological process of synthesizing (building up) lipids (fats) from acetyl-CoA or glucose, primarily for energy storage in adipose tissue.

lipolysis = the the biological process of breaking down lipids (fats) into glycerol and free fatty acids, typically for energy production in the body.

Lipogenesis: Building fat (synthesizing fatty acids and storing them as triglycerides).

Lipolysis: Breaking down triglycerides (stored fat) into fatty acids and glycerol for energy.

free fatty acids versus triglycerides

FFA: circulate in the bloodstream and are used for energy

Triglycerides: stored fat in adipose tissue that is released during lipolysis

What are the two key adipokines?

As we increase in the number of fat cells, what happens to adiponectin and leptin production?

What happens to the adiponectin:leptin ratio?

Adiponectin: improves insulin sensitivity

Leptin: satiety and insulin inhibition

increased hypertrophic fat storage = decreased adiponectin and increased leptin

the bigger the fat cell the lower the adiponectin to leptin ratio because there is more leptin and less adiponectin

How do the sex steroids affect the expression of LPL?

Androgens increase fat storage (LPL expression) in visceral cavity (visceral fat)

Estrogens increase fat storage (LPL expression) in the breasts and hip/gluteal region (subcutaneous fat)

sex hormones tell the body where to express LPL

explain how PPAR gamma activates the process of adipogenesis? what is the process of adipogenesis?

When PPAR gamma is turned on and activating the process of adipogenesis, it is taking mesenchymal stem cells and committing them to the pathway of becoming a fat cell

process in which Pre-adipocytes contribute to fat cell population

Adipogenesis is the process by which precursor cells called preadipocytes differentiate into mature adipocytes (fat cells).

It includes:Proliferation: Preadipocytes divide and multiply.Differentiation: Preadipocytes mature into functional adipocytes capable of storing fat.

explain what factors contribute to hypertrophic adipose development

Certain foods and genetics

There are times when PPAR gamma isn't active---let's not make more fat cells, let's make them bigger (hypertrophy)

There are various dietary stimuli that can do that (the polyunsaturated fat, linoleic acid)

- Saturated fat abundant in so called "vegetable" oils

- Vegetable oils are actually refined seed oils

Linoleic acid and genetics can force cells to grow through hypertrophy*

explain the role genetic predispositions have on PPAR gamma and fat storage

there are populations within the globe that have more problems with diabetes (mexican-american)

Hispanic populations have a much higher rate of Type II diabetes which is a problem of insulin resistance. What we see is that they have a variant in PPAR gamma making it not work as well. Meaning, if they gain weight there is less adipogenesis (hyperplasia --> small, more abundant fat cells) and more lipogenesis (hypertrophy).

Hypertrophic fat cells are predominant and problematic (the bigger the fat cell, the more problematic because it causes inflammation and insulin resistance)

what are the two primary reasons we store fat

survival and reproduction

describe the relationship between fat storage and human survival

- humans are the only land mammal born obese because we require lots of energy for our brains

- One way to fuel our brain is by burning fat which makes ketones

- Ketones are a very good fuel for the brain

- Humans are born obese because fat is burnt for fuel and when a person's fat burning goes up, ketogenesis goes up and the brain has more energy (likes ketones)

what is the body's energy reserve? how is this beneficial for humans? How does it differ between the sexes?

fat

Fat tissue is primarily a reservoir of energy waiting to be used, but most people never really use it because they eat in a way that stores more and more energy rather than using it

In times of food scarcity, it's a good thing that we have an abundance of energy in fat. Any time calories stop coming in, we have another source of energy, fat, to fuel our bodies

average woman has 23 kilograms of fat/207,000 kcal, average man has 20 kilograms/180,000 kcal of fat which is a lot of energy to fuel the body

explain the relationship between fat and reproduction

- leptin is released from fat tissue

- leptin acts on hypothalamus and tells it to produce GnRH

- GnRH acts on the anterior pituitary and stimulates the release of sex-related hormones like LH and FSH

- LH and FSH act on the gonads and cause them to release sex hormones like estrogens and androgens

no fat = no leptin = no sex hormones = anovulation/no reproduction

If you don't have enough fat tissue you won't have enough energy to fuel the metabolic needs of reproduction so leptin won't be as abundant and sex hormones won't be released

what type of organ is fat tissue

Fat tissue is a very active hormone-producing organ (endocrine organ). Fat cells make many hormones, like leptin

where do we store fat?

almost anywhere that we have adipose tissue

different depose (storage sites) have different effects

what are the three general depose of fat humans have?

1. brown adipose tissue

2. subQ adipose tissue

3. visceral adipose tissue

explain the microscopic differences between brown fat, subcutaneous fat, and visceral fat

Subcutaneous and visceral fat look similar: both classified as white adipose tissue (Whitish-yellow fat)

Subcutaneous fat is more vascular (more blood vessels)

White fat cells have enormous lipid droplet with relatively fewer organelles that are squished up against the side

Brown adipose tissue: cells are very small and heavily loaded with mitochondria and nuclei

what are some differences between white adipose tissue and brown adipose tissue (size, makeup, and function)

a BAT is about a tenth of the size of a WAT

White fat cells have an enormous lipid droplet with relatively fewer organelles that are squished up against the side

In contrast, brown adipocytes are much more heavily loaded with small lipid droplets and mitochondria. These mitochondria are enriched with uncoupling protein 1 (UCP1)

both have lipid droplet(s), nuclei, and mitochondria

White adipose tissue is designed to store fat; brown adipose tissue is largely designed to use/burn stuff

what is the significance of UCP1 in brown fat

UCP 1 enables brown fat tissue to create so much heat

what makes brown fat more metabolically healthy

More brown fat = healthier metabolic profile

- Improved insulin sensitivity

- Protection against obesity

People who have more brown fat have a reduced risk of obesity and cardiometabolic problems (heart disease and type II diabetes)

how can brown fat be activated

Primary method of activating brown fat is through cold: cold showers, cold immersion

Anytime the body is cold and wants to shiver, brown fat will activate

difference in adipose tissue between babies and adults? why is it important?

As adults, we mostly have white adipose tissue. As babies we had a lot of brown adipose tissue. Brown adipose tissue is why babies don't shiver when cold to create heat. This is good because babies don't have a lot of muscle. A healthy baby is a chubby baby. A lot of fat is brown fat which is making heat, so babies don't need to shiver.

explain the role of insulin and ketones on shifting adipose metabolism

Insulin will make brown fat cells act more like white fat cells: really slows down metabolic rate (storage > energy use)

In contrast, ketones make white fat tissue, which humans have so much of, start to act more like the hyperactive brown fat cells (burn fat > store fat)

Ketones and cold activate brown fat-type functions

what is one of the most important jobs of adipose tissue

fat storage

insulin versus LPL

insulin tells the body to store fat, but LPL tells the body where to store fat

explain the relationship between genetics, sex steroid hormones, and LPL

- genetics affect LPL expression

- sex steroid hormones affect LPL expression

- expression of LPL determines fat deposition

if estrogens tell the body where to store fat, not how much fat to store, why do women have more fat on their bodies than men?

Primarily it's a function of progesterone because progesterone loves to tell the body to store fat

progesterone increases fat storage and hunger

Progesterone is the hormone of gestation (pregnancy), so this makes sense because you have to have fat tissue to get pregnant and you have to have fat tissue to keep pregnancy

estrogen's role in fat storage/fat burning

Overall, estrogens are helpful in preventing fat storage from going too high which makes the women's body burn more fat

Women burn more fat than men, almost 50 percent higher

what makes fat grow

elevated insulin and sufficient energy

You have to have elevated insulin to tell the fat cell to grow, but then you need sufficient energy in the form of calories to fuel that growth; both are essential

explain why fat cells cannot grow without elevated insulin and sufficient energy

The fat cell, even though it has been swimming in an ocean of energy (glucose, fat, calories), does not know how to use said energy to grow without insulin telling it how

Insulin blocks fat from breaking down fat cell (into free fatty acids

If insulin is up it tells cell to grow and pulls energy (calories) in to fuel that growth ***

what does insulin tell fat cells to do

Pulls glucose and turns it into fat

Pulls fat in and turns it into triglycerides (which is the storage form of fat)

Blocks fat from breaking down the fat cell (stops lipolysis --> the breaking down of fat into free fatty acids)

what happens if calories are still high but insulin is low? how can fat cells shrink if energy isn't low?

two adjustments in the body are made

1. Increases metabolic rate

2. energy wasting

- if insulin is low, body starts wasting energy in the form of ketones in the breathe and urine (every ketone has a caloric value roughly similar to glucose)

- If insulin is low, blood glucose gets so high that glucose is urinated out

- If insulin is low, doesn't matter how many calories the person is eating, they begin dumping energy out of the body

- Perfect example of this is type I diabetes

in type I diabetes, EE is...

metabolic rate is 20% higher in people with type I diabetes

People with type I diabetes have a voracious appetite, but they can't store energy on their bodies because metabolic rate is way too high

People with type I diabetes are missing insulin. Every other hormone is there

who studied metabolism in severe diabetes

E.P. Joslin (endocrinology)

F.G. Benedict (metabolic rate)

how does the introduction of insulin affect metabolic rate for patients with type I and type II diabetes

metabolic rate slows

An absence of insulin = an absence of control over the metabolic rate

what is diabulimia

an eating disorder in which a person with type I diabetes deliberately under doses on insulin to stay thin

- if insulin is low, fat cells have to shrink

- you can eat as much as you want, but without insulin, your metabolic rate will be too high and your energy will be wasted from their bodies (glucose is expelled from body without being used for energy and your fat storage will be too low because your body is using it for energy)

what two things happen when an untreated type I diabetic gets insulin therapy

1. eat less

2. gain fat

why is rotating your insulin injection sites important

At the site of the insulin injection versus a few inches away, the fat cells getting all the insulin are much bigger (hypertrophy), so if you don't rotate you will have odd areas of fat accumulation

why is too much (hypertrophic) fat a problem

1. hypertrophic fat cells run out of room

- "no vacancy"

- becomes resistant to insulin to prevent further growth

- insulin normally inhibits lipolysis

2. hypertrophic fat cells "suffocate"

- If fat cells are too big, it pushes other fat cells further away from the capillary

- When they get too far, they can't get enough oxygen and suffocate (become hypoxic)

- small fat cells have sufficient blood flow from capillaries, but big fat cells don't

why is too little fat a problem

how do "suffocating" hypertrophic cells correct this problem

by activating inflammation: cytokines (small, inflammatory hormones) are released from fat tissue, causing inflammation in the body and the formation of new capillaries -- attempts to correct suffocation and hypoxia

what two specific processes do hypertrophic fat cells activate to ensure their survival, but that is harmful to the rest of the body

1. Fat cell becomes insulin-resistant to prevent further growth

2. fat cells becomes pro-inflammatory to try and correct the blood flow insufficiency

how do anti-diabetics work? what are they?

it forces fat tissue to become hyperplastic (to multiply and undergo hyperplasia), which takes this person who might've overwhelmed their threshold and actually increases the threshold

Improves insulin resistance and their type II diabetes gets better by making them fatter (telling their body to store fat in the right place--in the fat cells)

Activates PPR gamma encourages person to store more fat (in smaller, but more abundant fat cells) (healthier)

explain the relationship between certain ethnicities (specifically south asian) and the personal fat threshold

The personal fat threshold is extremely relevant as we look across ethnicities

- Caucasian individuals typically have more, but smaller fat cells (more hyperplastic fat growth)

- In contrast, south Asians have bigger fat cells (more hypertrophic fat growth)

- Therefore, Caucasians have a higher threshold (can store more fat and be healthier)

- south asians have less storage for fat accumulation

- they could have the same kilograms of fat but because the fat is stored differently, caucasians would have less health problems than south asians (more inflammation and more insulin resistance/type II diabetes)

T or F: how a person stores fat matters more than how much fat they store

TRUE

what role does progesterone play in fat cell formation

Progesterone stimulates new fat cell formation by activating PPAR-gamma/adipogenesis

- This happens on butt and hip region

- More fat cells = healthier fat cells

why is visceral adipose tissue so problematic

Visceral fat is so problematic because it only grows through hypertrophy

These fat cells tucked within visceral space, squished between internal organs do not grow through hyperplasia

Hypertrophic fat cells are pathogenic/disease-inducing; people with more visceral fat are at higher risk for disease

- insulin resistance

- type II diabetes

- heart disease

- fatty liver disease

- PCOS

- and more

how many adipokines are there

more than 50

what are adipokines

fat-derived hormones

what heavily influences adipokines

adipocyte size

describe adiponectin

Fat-derived hormone

The more a person is storing fat, particularly through hypertrophy, the less adiponectin they are making

Adiponectin acts throughout the body: helps fat cells be healthy, helps liver be healthy, helps muscle tissue be healthy

- works on adipose, liver, and muscle

Good metabolically healthy hormone

describe leptin

Also a good metabolically healthy hormone

As adiponectin goes down (as body starts to have bigger and bigger fat cells), leptin goes up

Bigger fat cells mean more leptin

Too much leptin can create a condition called leptin resistance where the leptin isn't working well

Leptin works in many different places: brain, adipose (fat cells that create it), beta cells (cells that produce insulin), and muscle

what is one way to determine the size of a person's fat cells

One way to determine the size of a person's fat cell is to look at their adiponectin to leptin ratio

If a person has bigger and bigger fat cells , they are making less adiponectin, but more leptin, thus, the bigger the fat cell the lower the adiponectin to leptin ratio

explain the leptin-insulin feedback loop

The interaction between leptin and insulin:

- Leptin wants to inhibit the beta cells from creating insulin

- Insulin will stimulate leptin production, but leptin will inhibit insulin production

- Insulin is necessary to tell fat tissue to grow: too much insulin promotes fat growth, too little insulin prevents any fat growth

- If leptin is working, it wants to keep insulin in check

- Other factors also stimulate insulin (such as eating glucose), but if you don't have any leptin, you have less of an inhibitory signal of insulin and thus insulin goes higher

T or F: there can be no obesity without hyperinsulinemia

TRUE

what is lipodystrophy

Genetic inability to store fat in fat cells on their body

there are two types:

1. generalized

2. partial

what is generalized lipodystrophy

- whole body

- Can be congenital (born with it) or acquired by drug or illness

what is partial lipodystrophy

- certain areas

- only congenital

what are the consequences of lipodystrophy

1. high adiponectin which reduces insulin sensitivity (more prone to type II diabetes)

2. low leptin which reduces satiety (hunger) and fertility

3. ectopic lipid storage

what medications may help with lipodystrophy and why?

leptin: regulates reproductive hormones better

PPAR gamma activators: tells body to store more fat

what enzymes are used for lipogenesis? which ones re-esterify FA into TG

[GPAT, DGAT], ACC, FAS

LPL

what is GPAT

glycerol 3-phosphate acytltransferase

what is ACC

Acetyl CoA carboxylase

what is FAS

fatty acid synthase

what is DGAT

diglyceride acetyltransferase

what is LPL

lipoprotein lipase

what is TSC

Tuberous sclerosis complex