Triglycerides and Leptin Resistance

Been reading a lot about leptin and leptin resistance lately and the recent theory that triglycerides cause leptin resistance.  Leptin is secreted by fat cells essentially in correlation to fat mass and it is supposed to tell us to stop eating when we have accumulated too much fat.  The leptin resistance theory of obesity is that our brains don't receive the leptin signal so we keep eating and get fatter.

Triglycerides Induce Leptin Resistance at the Blood-Brain Barrier

Abstract

Obesity is associated with leptin resistance as evidenced by hyperleptinemia. Resistance arises from impaired leptin transport across the blood-brain barrier (BBB), defects in leptin receptor signaling, and blockades in downstream neuronal circuitries. The mediator of this resistance is unknown. Here, we show that milk, for which fats are 98% triglycerides, immediately inhibited leptin transport as assessed with in vivo, in vitro, and in situ models of the BBB. Fat-free milk and intralipid, a source of vegetable triglycerides, were without effect. Both starvation and diet-induced obesity elevated triglycerides and decreased the transport of leptin across the BBB, whereas short-term fasting decreased triglycerides and increased transport. Three of four triglycerides tested intravenously inhibited transport of leptin across the BBB, but their free fatty acid constituents were without effect. Treatment with gemfibrozil, a drug that specifically reduces triglyceride levels, reversed both hypertriglyceridemia and impaired leptin transport. We conclude that triglycerides are an important cause of leptin resistance as mediated by impaired transport across the BBB and suggest that triglyceride-mediated leptin resistance may have evolved as an anti-anorectic mechanism during starvation. Decreasing triglycerides may potentiate the anorectic effect of leptin by enhancing leptin transport across the BBB.

Discussion (reformatted)

Here, we showed that:

Starvation-induced inhibition of leptin transport was caused by a circulating factor

The fat component of milk (which is 98% triglycerides) as well as specific triglycerides could induce inhibition of leptin transport across the BBB in vivo, in situ, and in vitro

The FFAs comprising those triglycerides were ineffectual

Manipulation of triglyceride levels with diet or fasting in normal or obese mice had an inverse effect on leptin transport

Reduction of triglycerides by pharmacological intervention reversed the impairment in leptin transport.

Taken together, these findings show that triglycerides directly inhibit the transport of leptin across the BBB and so could be a major cause of leptin resistance at the BBB.

Perhaps the article should have been entitled "Dairy triglycerides" or "Some", because one part of this study pitted milk fat against intralipid (veggie derived triglycerides - soybean oil-based source of triglycerides containing the essential FFAs linolenic and linoleic acid, purified egg phospholipids, and glycerol).  The milk-fat produced what is described as "an immediate long-lasting impairment in leptin transport", while the (Omega 6 rich) intralipid is described as being "without effect".  They also tested non-fat milk and got no response thereby implicating the triglycerides in milk fat as the culprit.

The other triglyceride that produced the transport effect were triolein (oleic acid, olive oil) that produced the effect at similar and lower doses.  Three others were tested DPOG (palmitate), DSOG (stearate) and DMOG (myristate).  The latter did not produce the effect while the other two (longer chain sat fats) did at similar doses as milk fat.

So to summarize:  The triglycerides that induced leptin resistance were longer chain commonly circulating saturated fats (palmitate, stearate) and MUFA (oleic).  While the shorter chain sat fat (myristate) and PUFA (essentially soybean oil) did not.  The free fatty acids (NEFA/FFA) of any of the triglycerides do not produce the effect.

One thing I find interesting is that short term fasting -- that reduces endogenous triglyceride levels -- does not induce leptin resistance, while starvation (48 hr fast) elevated triglycerides and produced the impaired transport effect.  In my crazy days I have fasted several days in a row and I can attest that hunger usually subsides somewhere after the 2nd day.  This is in contrast with leptin action, so it's not the leptin that is suppressing hunger in that scenario.  This is interesting to me because some describe leptin as the controller of all things having to do with maintaining homeostasis, and yet something else has to be responsible for greater hunger early in a fast and substantially reduced hunger in "starvation".  But if our ancestors got a bit pudgy, this makes sense in that theoretically their leptin levels should be elevated and so early in a fast leptin gets to the brain and suppresses hunger, but as the fast lengthens resistance builds so hunger builds.  Like I said, this makes sense, but contradicts what we pretty much know to be the case with fasting.  OTOH, if there's anything to this leptin resistance theory upsetting the fat-mass apple cart, it may explain why some have success doing intermittent fasting (IF).  The short term fasts would reduce the triglyceride levels for a sufficient period to reverse leptin resistance and allow the brain to "read" that the fat stores are still full? 

OK -- So ... what do we make of this?  The interpretation I've been reading is that HC diets elevate triglycerides, and LC diets lower them.  Therefore an LC diet should be ideal for reversing leptin resistance, re-setting one's metabolic homeostasis.  However this study pretty clearly illustrates that it is certain triglycerides circulating that induce the effect.  Therefore it would be total circulating trigs that would be associated with this.  Those eating even a lower fat version of LC, and especially those eating a higher fat version would have significant postprandial trig levels. 

Eating certain fats seems to inhibit the signal indicating one's level of stored fat.  Velly intellesting ...