As I am sure you are aware the majority of leptin is produced in adipose tissue. However, numerous other cytokines are produced in adipose tissue as well, the signal for the production of almost all of which is glucose influx. However, not all adipose cells are created equal. Adipose tissue can be subdivided into three disparate categories: Subcutaneous Adipose Tissue (SAT), deep-layer SAT, and Visceral Adipose Tissue (VAT). For our purposes, we will consider deep-layer SAT and SAT to be the same thing. It’s worth noting that men tend to store more fat in deep-layer SAT and women tend to store more fat in SAT. For the most part, these two types of tissue behave identically. The only major difference between the two is that deep-layer SAT tends to be slightly more responsive to NE-induced lipolysis. For the rest of this article, I will treat them as though identical.

Adipose Tissue Types: Difference between Visceral Adipose Tissue and Subcutaneous Adipose Tissue

VAT and SAT however are vastly different. Their respective physiology is summarized below.

Effecter VAT vs. SAT Effect
Catecholamine induced lipolysis VAT > SAT Increased fatty acid turnover in VAT
Anti-lipolytic effect of insulin VAT < SAT Increased fatty acid turnover in VAT
Glucocorticoid receptors VAT > SAT Elevated lipoprotein lipase activity
11-Beta-HSD-1 Activity VAT >> SAT Local conversion of corticosterone to cortisol
Leptin secretion VAT << SAT Lowered SNS regulation of VAT implies reduced insulin sensitivity
Adiponectin secretion VAT < SAT Lowered whole-body fatty acid oxidation and increased insulin resistance
Angiotensinogen secretion VAT >> SAT Enhanced pre-adipocyte recruitment
IL-6 secretion VAT > SAT Inflammation, Cardiovascular risk, and reduced IGF-1 signalling
Plasminogen Activator Inhibitor – 1 (PAI-1) VAT > SAT Cardiovascular risk
PPAR-gamma induced pre-adipocyte recruitment VAT < SAT PPAR-gamma mediates SAT cell number.
Cortisol, Androgen, and Angiotensin II induced pre-adipocyte recruitment VAT > SAT Androgens, Cortisol, and AngII determine VAT tissue distribution.
Apoptosis VAT > SAT VAT cells tend to go into cell death
Return to pre-adipocyte physiology VAT < SAT SAT cells tend to return to being pre-adipocytes instead of undergoing programmed cell death

Visceral Adipose Tissue (VAT)

Visceral adipose tissue is located in the abdomen behind the abdominal muscles, near your organs. Because of its location and altered cell physiology, VAT is tightly linked to Syndrome X/Metabolic Syndrome/Polycystic Ovarian Syndrome (PCOS)/Childhood Adrenal Hyperplasia (CAH). The collection of syndromes and diseases above all have one thing in common: elevated corticosteroid production and often elevated androgen levels in women.

Visceral adipose tissue is often associated with morbidity. This is attributed to the so-called portal vein theory. The portal vein theory states that because of VAT cell location, it dumps a lot of free fatty acids and adipokines into the portal vein. As stated above, the portal vein is responsible for non-insulin-dependent glucose disposal. The excess free fatty acids in the portal vein reduce glucose uptake and prevent this glucose disposal mechanism from operating properly. This results in hyperglycemia and elevated basal insulin levels throughout the day.

Furthermore, interaction at the liver with all of these cytokines alters the entire body’s physiology, leading to a host of unhealthy conditions such as high blood pressure, cardiovascular disease, cholesterol abnormalities, reduced insulin sensitivity, increased plasma glucose levels, hyperleptinemia, elevated plasma insulin, increased reactive oxygen species production, pre-mature death, etc.

Just as fat cell location is important, so too is adipose cell size. Normally, as adipose cells grow in size, they increase cytokine production and secretion linearly with respect to their volume. However, at a certain point, adipose cells seem to undergo a metabolic shift: the amount and type of cytokines they secrete changes. This so-called Hypertrophied Adipose Tissue (HAT) does not behave as expected. Not only does it alter its secretion patterns, but it also becomes insulin-resistant. Until recently it was not well understood how these changes were taking place, however, a very recent study sheds a lot of light on the issue.

For a long time, it was just assumed that more fat cells interacted with each other to alter adipose-derived hormone levels. Researchers believed that this interaction led to the alterations in adipose tissue physiology seen in the obese. However, a study by Le Lay et al. (1) seriously disputes this endocrine-centric perspective.

The mechanism these doctors proposed was one of altered cholesterol regulation. It has been identified that in HAT cells, cholesterol starts to appear in the perilipin encased lipid droplets. This is quite abnormal. Normally your body is not so keen on storing cholesterol. The authors proposed that as fat cell size increases, the amount of cholesterol present in the cell membrane relative to surface area decreases. The authors further suggest that because cell-derived cholesterol was not present in the membrane, it was free to interact in the fat cell, and that these interactions were regulating the HAT cell’s odd physiology.

To examine this behaviour they utilized unpopulated cyclodextrins. Cyclodextrins are a doughnut-shaped molecules; the outside ring is hydrophilic yet the inside ring is lipophylic. This is why they are often used to deliver lipid-based molecules like pro-hormones across mucus membranes. By using unpopulated cyclodextrins the scientists were able to literally rip the cholesterol out of the cell membrane to see what kind of effect it would have on adipose cell physiology.

What they found is summarized below:

Protein Cholesterol depleted vs. Standard adipose cells.
Genes positively regulated by cholesterol depletion –
Angiotensinogen 7
TNF-alpha 4.7
IL-6 3.4
SR-BI 3.5
Caveolin-2 2.6
GLUT1 2.6
FAS 2.3
Genes negatively regulated by cholesterol depletion –
ABC1 0.5
GLUT4 0.3
UCP3 0.2
Mildly unaffected genes –
G3PDH 1.9
A2-AR 1.9
Caveolin 1 1.8
PPAR-gamma 1.8
Perilipin 1.8
PAI-1 1.7
SCD-1 1.6
aP2 1.5
HSL 1.5
UCP2 1.4
B3-AR 1.2
Actin 1.1
VLDL receptor 1.1
Insulin receptor 1.1
Leptin 1.1
Fatty Acid Transolcase (FAT) 1.1
Id2 1.0
GAPDH 1.0
LPL 0.9
Id3 0.9
C/EBP-alpha 0.7

The mechanism behind this altered physiology was identified as a reversal of the serum responsible element-binding protein (SREBP) ratio, or the SREBP2/SREBP1a ratio. Normally SREBP1a is the dominant isoform of the SREBP family; it activates numerous gene promoters. SREBP’s are how foodstuffs bring about gene transcription.

The SREBP family is normally restrained in a holding cell in the endoplasmic reticulum. Insulin however frees SREBP’s to move about the cell and activate gene promoters through heterodimerization. SREBP1a is particularly interesting in that it promotes both the lipogenic hormone FAS and the lipolytic hormone leptin. What is fascinating is that what activates SREBP1a determines which of the two genes it promotes. If E-Box binding is promoted then FAS is transcribed but if SREBP is promoted then leptin is transcribed.

By reducing membrane cholesterol in adipocytes the SREBP ratio became inverted. As explained, SREBP1a is typically dominant. However, in the cholesterol-depleted cells, SREBP1a decreased, SREBP2 nearly doubled, and SREBP1c was unaltered.

These results taken together with those demonstrating increased VAT tissue provide a nice working example of what the adipose-derived endocrine profile of the obese looks like.

Of no surprise to you, I am sure, as a person slowly overeats their fat cells grow. This causes linear elevations in adipose-derived cytokines to be present in the blood. This ideally serves to induce the rest of the body to burn off this excess stored energy, though it is ill-equipped to handle this task when people continually and chronically overeat. Eventually, the cell reaches a point where it no longer populates the membrane with cholesterol. Because of this, we end up with the nasty endocrine profile summarized above. The large increase in angiotensinogen—a strong regulator of VAT cell growth—is particularly disturbing. Along with this VAT growth, hypertrophied fat cells also promote high blood pressure. Taken together this hormonal profile induces insulin resistance, hyperglycemia, and hyperinsulinemia, all of which promote a slow metabolism and metabolic deregulation.

Reference:

Le Lay S, Krief S, Farnier C, Lefrère I, Le Liepvre X, Bazin R, Ferré P, Dugail I. Cholesterol, a cell size-dependent signal that regulates glucose metabolism and gene expression in adipocytes. J Biol Chem. 2001 May 18;276(20):16904-10. doi: 10.1074/jbc.M010955200. Epub 2001 Feb 27. PMID: 11278795.