Insulin mimesis and NOX enzymes (3) MCT

So now it's time to see how it is possible to understand the obesogenic effects of fully hydrogenated coconut oil in Surwit diets and also the recognised potential for MCT induced weight loss effects. Oooh, another paradox!

I've been skirting around this subject for years and I still do not have nice solid answers but this is getting closer.

It's worth thinking, initially, about fructose as a weight loss agent.

Inclusion of low amounts of fructose with an intraduodenal glucose load markedly reduces postprandial hyperglycemia and hyperinsulinemia in the conscious dog

Going back to this canine model of intraduodenal glucose infusion +/- 5% fructose we have these curves:

The fructose supplemented line (open circles) shows a markedly reduced insulin excursion, a direct result of the reduced penetration of glucose past the liver. Fructose, acting solely at the liver, is imitating insulin via ROS from an NADPH oxidase. Glucose gets stored:

The pancreas sees a markedly reduced glucose level, so responds with a markedly reduced insulin secretion (200pmol/l down to 100pmol/l).

If you were an adipocyte in the periphery you are not going to see the fructose acting as insulin via ROS to sequester glucose as hepatic glycogen. This all happens in the liver. All an adipocyte sees is 100pmol/l of insulin instead of 200pmol/l.

What is that going to do to your rate of lipolysis?

I would expect it to be higher in the fructose supplemented state.

Aside. There is s small rise in lactate with the fructose infusion but I doubt it would offset an halving of the insulin level. End aside.

Does this cause weight loss? I don't know that anyone has asked that question in this form for humans using fructose. 

Acetate, which I consider to induce a similar signalling response to fructose, certainly does. Drinking vinegar for weight loss appears to work. The effect is not huge but appears real and is mechanistically logical:

Vinegar intake reduces body weight, body fat mass, and serum triglyceride levels in obese Japanese subjects

So maybe fructose is a weight loss drug, in modest amounts, on a background of a starch/linoleic acid diet.

So if we get back to medium chain triglycerides for weight loss, here they used either coconut oil or MCT oil (both worked):

Coconut oil and medium-chain fatty acids attenuate high-fat diet-induced obesity in mice through increased thermogenesis by activating brown adipose tissue

You can get a marked decrease of weight gain in a (mouse) model of lard-driven obesity by small amounts of MCTs.

Like fructose and to some extent acetate, low doses of MCTs are predominantly diverted directly to the liver via the portal vein from the gut. If they generate modest doses of ROS, ie at insulin mimetic levels, in the liver alone, they will allow the diversion of glucose in to hepatic storage and so reduce penetration of glucose to the systemic circulation and that will reduce the need for insulin secretion. Peripheral adipocytes will see less insulin and so store less, or release more, fatty acids.

To me that makes sense. Increasing hepatic insulin-like signalling derived from very modest MCT ROS generation protects the peripheral adipocytes from glucose/insulin exposure.

Exposure to higher levels of MCTs, ie Surwit-like diets, is undoubtedly obesogenic.

As we increase the proportion of MCTs in the diet this gut-to-liver channel increases delivery giving increased storage of glucose as hepatic glycogen (no problem) and an attempt at hepatic storage of MCT fatty acids. But MCTs aren't stored, they are rapidly oxidised to give ketones plus mitochondrially derived ROS. At high enough exposure there will be enough ROS to finally resist insulin signalling within the hepatocytes.

Hepatic insulin resistance allows more insulin to penetrate past the liver to the systemic circulation and so to reach peripheral adipocytes. It's not essential for MCTs per se to reach those adipocytes in any quantity, though if they do so at insulin mimetic levels they will compound the problem.

Back in March this year I pointed out how mixed coconut MCTs at "physiological" concentration are experimentally confirmed generators of ROS at a level which will phosphorylate Akt in isolated neurons, insulin mimesis. I was also clear that "supra-physiological" exposure to octanoate inhibited correct development of adipocytes, ie caused insulin resistance. These effects applied to hepatocytes, which are the primary target of dietary MCTs, would be quite enough to explain the Surwit effects and weight loss effects, depending on dose.

Summary: Low dose MCTs are insulin-mimetic and primarily delivered to the liver only. They protect peripheral adipocytes from insulin exposure and allow weight loss/limit weight gain.

High dose MCTs provide insulin resistance levels of ROS in hepatocytes and facilitate insulin's penetration to peripheral adipocytes. Any low levels of MCTs reaching peripheral adipocytes will provide low levels of ROS to augment fat storage by insulin per se.

It is perfectly possible to generate obesity with highly saturated MCT based diets. Even at 2% linoleic acid.

Peter