My approach to chronic disease has been to look for underlying pathologies. Obesity and insulin resistance (IR) share a lot in common, including underlying pathologies. They are both responses to energy overload, seem to be mainly caused by mitochondrial dysfunction and/or inflammation, and SOCS3 and PTP1B increase both leptin resistance (obesity) and insulin resistance . So it makes sense then that most people who are overweight are also insulin resistant, and measures that cause weight loss also improve insulin sensitivity.
But what about those who are overweight but are insulin sensitive* and those who have a normal weight but are insulin resistant? Surely this is a paradox. Robb Wolf has said something like ‘there are no paradoxes in biology, just an incomplete understanding’. So the purpose of this blog post, like pretty much all the others, is to improve my understanding
* Roughly 25% of people with a BMI greater than 35 (obese) are insulin sensitive 
Differences between Insulin Resistant and Insulin Sensitive Obesity
Rather than just being an academic exercise, this is an important question as people with insulin resistant obesity have a higher risk of disease than people with insulin sensitive obesity  . A good place to start for an explanation would be to find out about the differences between them. People with insulin resistance obesity have:
- More abdominal fat (abdominal obesity/apple-shaped) 
- Higher markers of oxidative stress and inflammation in adipose tissue and plasma  
- Lower AMPK, PGC-1α  and adiponectin 
- High intramyocellular lipids (IMCL)* and hepatic lipids 
- Larger but fewer adipocytes  
- Higher HIF-1α (a signal of hypoxia) 
- Impaired adipogenesis (growth of new adipocytes) 
- Macrophage infiltration in adipocytes  and higher
ratio of M1 (pro-inflammatory) to M2 (anti-inflammatory) macrophages 
* Many athletes have very high IMCLs yet are insulin sensitive. But athletes don’t have much body fat and have a really good aerobic metabolism. The difference seems to be that athletes store IMCLs in such a way as to promote efficient utilisation (probably smaller droplets?) 
** The level of adiponectin and macrophages in adipose tissue strongly predicts insulin resistant obesity (r2=0.98) 
Insulin Resistant Obesity
In insulin resistant obesity what appears to happen most of time is this: adipocytes keep filling up with triglycerides and get larger until they can’t store anymore, and in the process they become progressively more insulin resistant. Insulin resistance is a signal of energy overload and impairs insulin’s actions of depositing triglycerides and suppressing FFA release from adipocytes, which leads to high circulating triglycerides and FFA .
The saturated FFAs (mainly palmitate) bind to TLR4 on macrophages and activate them, which is followed by NFκB release, an inflammatory cascade and macrophage infiltration in adipocytes. Reactive oxygen species (ROS) are also released in response to energy overload and oxidative stress can initiate a similar inflammatory cascade. TNF-α (activated by NFκB) increases lipolysis, the first of many vicious cycles 
Some of the mechanisms whereby FFA, ROS and inflammation increase insulin resistance are by reducing the activity of insulin sensitisers such as AMPK and adiponectin and activating JNK . AMPK  and adiponectin  have other beneficial effects such as reducing oxidative stress and inflammation (another vicious cycle).
While the abdominal adipocytes (in particular) are filling up and getting larger hypoxia (low oxygen) may result from the vascular not being able to keep up and/or from the adipocytes becoming too large for oxygen diffusion to work well . HIF-1α is a signal of hypoxia, is elevated in adipose tissue in people with obesity (more so in insulin resistant obesity) and reduces after surgery-induced weight loss. HIF-1α promotes inflammation, macrophage infiltration, mitochondrial dysfunction and endoplasmic reticulum stress, reduces adiponectin and may cause adipocyte cell death which leads to further FFA release 
Meanwhile the elevated FFAs and triglycerides in circulation are deposited in the liver and muscles (not the blood vessels*). Elevated triglycerides in the muscles/liver increase muscle/liver insulin resistance .
* For information on cardiovascular disease and atherosclerosis follow the links on this post
** See the flowchart below for a summary of the mechanisms involved