Further Adventures with Leptin

I mentioned a few of the working hypotheses for avoiding leptin resistance in my posts last week, including fructose and lectin avoidance, getting adequate nightly sleep, and eating at or above maintenance levels – or at least throwing in periodic carb refeeds – but there’s even more involved in establishing a good relationship with your leptin levels and leptin sensitivity. Depending on your general approach to life, this could be good news or bad news. It’s either more stuff to worry about, or more ways to buttress your health. As I alluded to last week, experimenting with carb refeeding and leptin manipulation within the broader Primal Blueprint eating style is butter on the steak (because “icing on the cake” just won’t do for us Primal folks).

(Excessive, Heavy-handed, Omega-6 Influenced) Inflammation and Leptin Resistance

As if you needed another reason to avoid chronic, systemic inflammation (heart disease, weight gain, and cancer weren’t enough for ya?), it seems that inflammation also plays a role in leptin resistance.

Excessive inflammation has always been strongly associated with insulin resistance, obesity, and other hallmarks of the metabolic syndrome. It figures into pretty much everything we do and everything we experience. Lifting heavy things and breaking down muscle fibers elicits an inflammatory response. It’s beneficial if we do enough, but harmful if we do too much. Inflammation helps heal wounds; it’s how our body responds to stressors. Too much inflammation can cause disease, but inadequate amounts can also be dangerous. Leading a healthy, productive existence, then, requires finding a balance between pro-and-anti-inflammatory states. The average SAD eater dealing with stress induces entirely too much stress on his or her body, so we can safely assume that pro-inflammatory states are the issue here.

Interleukin-6 (IL-6) is one of the more potent agents of the body’s inflammatory response. This particular cytokine is well-known for mediating fevers and managing the acute phase response of our immune system. When tissue concentrations of fat are weighted toward omega-6 (like most people eating a modern diet high in omega-6 fats), excessive amounts of IL-6 are created in the inflammatory response. IL-6 is necessary, sure, but (surprise, surprise) too much is dangerous. Remember, these aren’t intelligent micro-organisms making decisions based on your welfare; they’re simply doing what they’re programmed to do by the signals you help provide. If you unleash a horde of IL-6, they’re going to wreak havoc because that’s what they’re supposed to do. Everything has a reaction, of course, and the body’s reaction to IL-6 (especially large amounts of it) is to release something called suppressor of cytokine signaling (SOCS), which is designed to downregulate cytokine activity once the job is done.

SOCS-3, a variety of SOCS, has an interesting relationship to leptin. After leptin has been secreted and runs its course, SOCS-3 is released to bind to the leptin receptor and downregulate leptin signaling. This is normal, physiological leptin resistance; it’s not necessarily pathological. Mice without the genes for SOCS-3 synthesis, for example, are remarkably sensitive to leptin, and obese, hyperleptinemic, leptin-resistant rats were given SOCS-3 inhibitors (an inhibitor of a suppressant; is that a double negative?) to increase fat burning and lose weight. But when you’ve got a guy or gal eating a terrible diet and leading an unhealthy lifestyle with high tissue concentrations of omega-6 fatty acids, suffering from steady levels of systemic inflammation which release tons of IL-6 and leptin receptor-binding SOCS-3, leptin resistance becomes pathological.

Minimize omega-6 intake, cut out the vegetable oils, and restore the tissue balance by eating fish or taking fish oil (ignore the word of caution regarding “obesity causing high fat diets,” for yours is certainly not) so that your inflammatory response system is more reasonable – and less apt to wreak collateral damage. Avoid excessive levels of inflammation, whether diet-induced or exercise-induced. No Chronic Cardio, no overtraining.

Okay, the big one is out of the way. Here’s another, smaller consideration to keep in mind.

Leptin Resistance and Insulin Resistance

If you remember from last time, refeeds are to be carb-based, rather than fat or protein-based, because carbohydrate stimulates greater leptin secretion. Why is that? Insulin stimulates leptin release. Yes, insulin begets leptin. Insulin releases in response to food intake, leptin releases in response to insulin, and the rest of the body “knows” that energy levels are adequate. In the healthy individual, this arrangement goes swimmingly, and appetite is reduced. The problem, of course, is that nature never envisioned an epidemic of insulin resistance. See, most folks trying do the right thing by CW to get healthy and lose weight are insulin resistant with high serum levels of circulating insulin. Chronic levels of insulin are going to produce chronic levels of leptin. Hello, leptin resistance.

Of course, elevated serum leptin predicts the onset of obesity and insulin resistance, so this is just another one of those vicious hormonal cycles in which modern eaters seem to find themselves entangled. Leptin resistance (from lectins, or elevated triglycerides, or systemic inflammation and omega-6 heavy tissue composition) leads to insulin resistance leads to more leptin resistance leads to… you see where this is going.

Researchers are still teasing out the full extent of leptin’s impact on the body’s inner workings, so I imagine there’ll be more posts in the future. Until then, sleep well, exercise smartly, eat Primally, and pass on the sugar, stress, seed oils, and spelt (yeah, yeah, it’s an obscure, archaic grain, but I felt like alliterating).

TAGS:  hormones

About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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29 thoughts on “Further Adventures with Leptin”

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  1. ”Until then, sleep well, exercise smartly, eat Primally, and pass on the sugar, stress, seed oils, and spelt ”

    it’s amazing how those choices can make about anyone healthier. It’s really simple when you think about it…

    thanks for the post.

    1. Because it occupies enzyme pathways without giving you remotely close to the same bang for your buck as omega 3 fish oils (or any of the omega 3 derived from grassfed beef).

      1. Jamie, good point. Also, plant based omega-3 has to be converted by your body to usable form. In a survey, 40 out of 46 store bought flax oil turned out rancid.

  2. Regarding excessive inflammation, I bet a highly plant based would also help. I always tell my clients, especially the ones who are 30+, that the three foods to focus on are veggies, fruits, and nuts. By focusing our nutritional foundation on these foods we douse ourselves in antioxidants, thus decreasing inflammation in our bodies.

    1. Susan, you mention on your site that a diet high in animal products is detrimental to health. I would be interested in seeing some evidence to that.

    2. Susan,

      Depending on the nut and the amount consumed, they could easily add to the omega 6 inflammation profile Mark discusses above.

    3. All nuts have horrible Omega 3:6 rations and a lot of them have dangerously high levels of PUFAs

  3. Perhaps a petty thing Mark, but you need a hyphen in “obesity-causing high fat diets” to make yourself properly understood. Oh, and keep up the good fight and all that!

  4. Is there anything that going Primal does not benefit?

    I am having trouble thinking of anything…

    Leptin resistance is just another thing to add to the list 🙂

  5. Hey Mark, I must say that I have really enjoyed the last three articles related to leptin. I particularly liked your analogy between those who play with their hormonal reactions and computer hackers who play with code. It was brilliant 🙂

    For those of us long-time PB’ers who are also the ‘hacker’ types, these kinds of articles are pure gold.

    Keep them coming.

    I for one am going to play around with carb-refeeding in the coming months. Will keep you posted on the results.

    Thanks once more,

  6. I also loved your computer hacking analogy =) Thanks for the articles!

  7. This is an interesting subject.

    I’ve recently noticed that after months of following a Primal lifestyle my appetite is voracious; I regularly exceed 1500 calories a meal, at least twice a day. I partly attribute this to a theory of mine, that in Grok’s day it was beneficial to eat excessive calories in times of plenty to prepare for the times of famine (high fat, moderate protein – based calories). Could Leptin production be a related factor to keep us from gorging on too many insulin producing foods (fruits for example)?

  8. Awesome post, Mark! Looks like I won’t be going raw vegan after all.

  9. Damn. You are killin’ it with these leptin posts recently.

    Thanks for the carb refeeding post especially. I know this site has a definite “low carb” swing to it, but you’ve always made it clear that “what works” is more important than “what’s supposed to work.”

  10. @ Susan– If I eat less oxidized foods, does that mean I can skip dousing myself in antioxidants? I’m just sayin’…

  11. Wow! These posts have been fantastic. I really love the posts on hormones, how they work for and against us and how we can help them in the right direction. (Same with the gene expression stuff and… well, all of it really! It’s all awesome info.) It just fascinates me and bolsters my determination to pay attention and get this primal thing right!

    I truly love what you do for us Mark – this is the only website I make sure to come to on a regular basis. It’s simply a must to read and absorb (even if I don’t comment enough).

    Thank you so very, very much! Oh, and… Grok on!!!

  12. So, when blueberry season comes around, I don’t have to pretend to be ignoring it? Cool, because life is too short not to go for the blueberries.

  13. I also found it interesting that the same type of cycle of leptin and insulin resistance found in overweight individuals was also present in people that were starving in other countries. Seems to be the basic model for when the body feels it needs more fat for its own survival.

  14. Love, love, love these posts on leptin. Thank you so much for painstakingly describing a complex process in simple terms. I definitely notice my hunger subsides and I have a resurgence of energy after a “refeed” (what I used to berate myself for as a cheat meal). Typically, this is followed with a very light eating day and some resistance to burn out the glycogen. It seems to cycle naturally, as I am less hungry the next day. Interestingly, on a low-sugar but whole-grain diet, if I binged on sugar and refined or even whole-grain carbs one day, I was voracious afterward and the whole next day. I seem to still have a lot of hunger triggered after the refeed, but the next day am not hungry instead. Maybe I’ve regained some lost leptin sensitivity since cutting out grains? That would be awesome! 🙂 Thanks for all that you do Mark. I love to visit your site daily around lunch, and look forward to the new post all morning.

  15. Okay…so I am clearly insulin resistant and leptin resistant to some degree being 5’7 and 100 lbs overweight and have very slow metabolism. I have autoimmune thyroid issue as well as autoimmune urticaria. I have been guilty of over training and training hard with heavy weights and eating almost zero carbs. Which didn’t cause weight loss but did narrow my waist a bit. Should I then be giving all that up in favour of long, slow walks and the occasional carb refeed?? I am so confused…

    1. It did also take a long time for me and my muscle to recover from a hard workout…I’d be sore easily a week after a training session. And in my health ignorant days I would just train anyways despite the groaning muscles…

    2. Sarah,
      I am also autoimmune urticarial and would love to communicate with you to see what’s working.

  16. It seems more logical to me that insulin resistance occurs before leptin resistance, especially if “insulin begets leptin”

    Insulin resistance leads to higher fasting serum insulin levels. Higher insulin levels lead to more leptin being “begotten” – more than needed, which eventually leads to leptin resistance.

    And most of the things that people recommend to counter leptin resistance – e.g. sufficient protein and fat soon after waking; don’t eat too soon before sleeping; good night’s sleep; possibly IF or at least fewer meals and no snacking; resistance exercise; HIIT; oh yes, and restricted carbohydrates – would all tend to reduce insulin resistance as well, so perhaps it’s a little academic anyway.

  17. Just a quick question ~ is coconut oil ok,which oils would be the best
    I love that fact that your information is based on research & you are not funded by any special interest group.

  18. I just wanted to say how great your site is. When I find some new information on the web and find it interesting, I always come back to your site and find what you stated about the same subject. At 51 I find lots of information on diet and exercise but sometimes it is crazy stuff the younger people are doing.