Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity.

Source

Department of Internal Medicine, University of Texas Southwestern Medical Center, Touchstone Center for Diabetes Research, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Roger.Unger@utsouthwestern.edu

Abstract

Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin.

PUBMED ARTICLE

Finishing off this paper, part III discusses leptin, fat location, obesity as a symptom, why rodents = people for these research purposes, and how America has been a sort of dietary experiment for the last 50 years. Part IV will be just going over some of the figures in this paper. Then we’ll be on to a new paper!

What’s Leptin Doing?

Only one thing causes leptin to be secreted in large quantities, and that’s the expansion of adipocytes (fat cells) after overeating. As soon as 24 hours after overeating, leptin levels rise along with increases in body fat, and this increase (as was covered in part II) is a defense mechanism to prevent fat from building up in all the wrong places (ie your organs).

An experiment was done by Lee et al. where two types of rats were fed two different types of diets. The normal (also known as the control group) rats were fed a high fat (60%) diet. The mutant rats (called Zucker Diabetic Fatty (ZDF) rats; also known as the experimental group) were fed a very low fat (6%) diet. These ZDF rats have a genetic mutation that makes their leptin receptors not respond, regardless of leptin levels. The results were astounding – the normal rats that gained weight had all of their fat in the proper place, the adipocytes. The ZDF rats on their low fat diets had their non-adipose organs overloaded with fat (triglycerides)! These findings support the thought that leptin is responsible for making sure fat gets stored in the right place.

When It Comes to Fat, It’s Location, Location, Location…

Lipids can cause death of normal cells – and for evidence, we turn to our friend the ZDF rat. The pancreas contains fancy sounding Islets of Langerhans, which contain hormone producing cells including beta-cells that produce insulin. ZDF rats have an increase in lipids (fats) getting deposited on the islets, and this is related to these beta cells losing their ability to function and the eventual loss of these cells themselves. In an in vitro (ie in a dish, not in a living creature) experiment, isolated islets were mixed with long chain fatty acids and they became damaged and eventually died. These two findings suggest that type 2 diabetes in these ZDF rats may be caused by too much fat landing on the islets.

Chiu et al. created another animal model to show that fats in the wrong place cause cell death. They made transgenic (transgenic means that their DNA was specifically changed by the scientists) mice that had an enzyme in their heart muscle cells (cardiomyocytes) that increased the amount of lipids transfered into these heart cells. They found that these heart cells had a large increase in lipids (duh, that’s what they were designed to do), and this lead to death of these heart cells and eventually early death of the mice. These problems were prevented if the investigators gave the mice doses of leptin (causing hyperleptinemia). This model shows that when excess fat gets deposited in the wrong cells, it destroys them, but this depositing/destruction can be prevented by leptin.

Okay, so Obesity is an Early Sign of Metabolic Syndrome to Come!

Yes, but not always. Some people are born with lipodystrophy, where they don’t have adipocytes – and when there are no adipocytes, there is no leptin, and without leptin there is no signal to stop eating and no signal to tell fat to get stored in the right place. In these individuals, the signs of metabolic syndrome occur much earlier than with obesity. For individuals with diet-caused obesity, it usually takes years of the body battling poor nutrition before metabolic syndrome develops. There may also be people between these two extremes – people who have adipocytes, but they don’t work 100% properly. These people might have what Dr. Ruderman described as “metabolically obese, normal weight syndrome.”

Wait! Most of This Research Was Done in Rodents! People Aren’t Rodents…

You’re absolutely right – people are not rats/mice. However, we are both mammals and have an astounding number of shared genes. Nature doesn’t recreate the wheel, so often times organs in many different animals do almost identical things. In this case, there are many similarities between rodent and human metabolic syndromes that suggest that, in this case, rats are people too:

1) The same organs are damaged in human and rodent metabolic syndrome

2) Humans and rats that have a genetic defect in their fat cells from birth both show fats being stored in the wrong places.

3) If you take the humans and rats from point #2 and give them leptin, you get a reversal of many of the syndrome’s problems

4) In humans and rodents, insulin resistance can be caused by lipids accumulating in the organs/tissues that insulin usually targets (liver/muscles).

5) Mislocated lipids have been found in heart, liver, muscle and pancreas of overweight and obese humans and rats.

If We Think of the USA (300 Million Subjects) as a 50 Year Dietary Experiment…

After 50 years of cheap high-fat high-carb foods brought to us by the revolution in the food industry, we have 200 million people overweight and more than 50 million with metabolic syndrome.

This brings us to a conundrum – one possible solution would be to raise the price of high fat high carb foods, making them much less convenient and desirable. The problem with this solution is the possible socioeconomic ramifications – what about the poor? No one is saying that the poor should eat these foods, but if prices are raised, then getting food would become a large problem, especially for low income people with many mouthes to feed. Whatever the case, it is clear that the standard American diet, combined with over eating and sedentary lifestyles, is killing us.

Read Part I Read Part II