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Further Adventures with Leptin

Posted By Mark Sisson On June 21, 2010 @ 9:44 am In Carbs,Diet,Health,Nutrition,Weight Loss | 27 Comments

I mentioned a few of the working hypotheses for avoiding leptin resistance [7] in my posts last week, including fructose [8] and lectin [9] avoidance, getting adequate nightly sleep, and eating at or above maintenance levels – or at least throwing in periodic carb refeeds [10] – 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 [11], obesity, and other hallmarks of the metabolic syndrome. It figures into pretty much everything we do and everything we experience. Lifting heavy things [12] and breaking down muscle fibers elicits an inflammatory response. It’s beneficial if we do enough, but harmful if we do too much. Inflammation [13] 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 [14] 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 [15] (like most people eating a modern diet high in omega-6 fats), excessive amounts of IL-6 are created [16] 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 [17], and obese, hyperleptinemic, leptin-resistant rats were given SOCS-3 inhibitors [18] (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 [19], and restore the tissue balance [20] by eating fish [21] or taking fish oil [22] (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 [23], no overtraining [24].

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 [25]. Insulin releases in response to food intake, leptin releases in response to insulin [26], 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 [27], 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).


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[7] avoiding leptin resistance: http://www.marksdailyapple.com/leptin/

[8] fructose: http://www.marksdailyapple.com/leptin-fructose-appetite/

[9] lectin: http://www.marksdailyapple.com/lectins/

[10] carb refeeds: http://www.marksdailyapple.com/carb-refeeding-and-weight-loss/

[11] insulin resistance: http://www.marksdailyapple.com/diabetes/

[12] Lifting heavy things: http://www.marksdailyapple.com/category/lift-heavy-things/?submit=view

[13] Inflammation: http://www.marksdailyapple.com/inflammation/

[14] stress: http://www.marksdailyapple.com/how-stress-can-make-you-fat/

[15] weighted toward omega-6: http://www.marksdailyapple.com/omega-3-fatty-acid/

[16] excessive amounts of IL-6 are created: http://www.ncbi.nlm.nih.gov/pubmed/12578976?dopt=Abstract

[17] are remarkably sensitive to leptin: http://www.nature.com/nm/journal/v10/n7/abs/nm1072.html

[18] leptin-resistant rats were given SOCS-3 inhibitors: http://www.springerlink.com/content/01125u6h41982562/

[19] vegetable oils: http://www.marksdailyapple.com/healthy-oils/

[20] restore the tissue balance: http://www.ncbi.nlm.nih.gov/pubmed/16239836?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_SingleItemSupl.Pubmed_Discovery_RA&linkpos=4&log$=relatedreviews&logdbfrom=pubmed

[21] eating fish: http://www.marksdailyapple.com/salmon-factory-farm-vs-wild/

[22] taking fish oil: http://www.marksdailyapple.com/fish-oil-health-benefits/

[23] Chronic Cardio: http://www.marksdailyapple.com/chronic-cardio-2/

[24] overtraining: http://www.marksdailyapple.com/how-to-deal-with-overtraining/

[25] insulin begets leptin: http://jcem.endojournals.org/cgi/content/abstract/94/8/2900

[26] leptin releases in response to insulin: http://ajpcell.physiology.org/cgi/content/full/283/1/C244

[27] elevated serum leptin predicts the onset of obesity and insulin resistance: http://wholehealthsource.blogspot.com/2008/04/leptin-and-lectins.html

[28] PrimalCon Oxnard 2014: http://www.primalblueprint.com/product/PrimalCon_Oxnard_2014/Events

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