Beyond Ötzi: European Evolutionary History and its Relevance to Diet. Part I

In the previous post, I explained that Otzi descended in large part from early adopters of agriculture in the Middle East or nearby.  What I'll explain in further posts is that Otzi was not a genetic anomaly: he was part of a wave of agricultural migrants that washed over Europe thousands of years ago, spreading their genes throughout.  Not only that, Otzi represents a halfway point in the evolutionary process that transformed Paleolithic humans into modern humans.

Did Agriculture in Europe Spread by Cultural Transmission or by Population Replacement?

There's a long-standing debate in the anthropology community over how agriculture spread throughout Europe.  One camp proposes that agriculture spread by a cultural route, and that European hunter-gatherers simply settled down and began planting grains.  The other camp suggests that European hunter-gatherers were replaced (totally or partially) by waves of agriculturalist immigrants from the Middle East that were culturally and genetically better adapted to the agricultural diet and lifestyle.  These are two extreme positions, and I think almost everyone would agree at this point that the truth lies somewhere in between: modern Europeans are a mix of genetic lineages, some of which originate from the earliest Middle Eastern agriculturalists who expanded into Europe, and some of which originate from indigenous hunter-gatherer groups including a small contribution from neanderthals.  We know that modern-day Europeans are not simply Paleolithic mammoth eaters who reluctantly settled down and began farming. 

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Lessons From Ötzi, the Tyrolean Ice Man. Part I

This is Otzi, or at least a reconstruction of what he might have looked like.  5,300 years ago, he laid down on a glacier near the border between modern-day Italy and Austria, under unpleasant circumstances.  He was quickly frozen into the glacier.  In 1991, his slumber was rudely interrupted by two German tourists, which eventually landed him in the South Tyrol Museum of Archaeology in Italy. 

Otzi is Europe's oldest natural human mummy, and as such, he's an important window into the history of the human species in Europe.  His genome has been sequenced, and it offers us clues about the genetic history of modern Europeans.

Otzi's Story

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New Obesity Review Paper by Yours Truly

The Journal of Clinical Endocrinology and Metabolism just published a clinical review paper written by myself and my mentor Dr. Mike Schwartz, titled "Regulation of Food Intake, Energy Balance, and Body Fat Mass: Implications for the Pathogenesis and Treatment of Obesity" (1).  JCEM is one of the most cited peer-reviewed journals in the fields of endocrinology, obesity and diabetes, and I'm very pleased that it spans the gap between scientists and physicians.  Our paper takes a fresh and up-to-date look at the mechanisms by which food intake and body fat mass are regulated by the body, and how these mechanisms are altered in obesity.  We explain the obesity epidemic in terms of the mismatch between our genes and our current environment, a theme that is frequently invoked in ancestral health circles.

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What Causes Insulin Resistance? Part IV

So far, we've explored three interlinked causes of insulin resistance: cellular energy excess, inflammation, and insulin resistance in the brain.  In this post, I'll explore the effects on micronutrient status on insulin sensitivity.

Micronutrient Status

There is a large body of literature on the effects of nutrient intake/status on insulin action, and it's not my field, so I don't intend this to be a comprehensive post.  My intention is simply to demonstrate that it's important, and highlight a few major factors I'm aware of.

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What Causes Insulin Resistance? Part I

Insulin is an ancient hormone that influences many processes in the body.  Its main role is to manage circulating concentrations of nutrients (principally glucose and fatty acids, the body's two main fuels), keeping them within a fairly narrow range*.  It does this by encouraging the transport of nutrients into cells from the circulation, and discouraging the export of nutrients out of storage sites, in response to an increase in circulating nutrients (glucose or fatty acids). It therefore operates a negative feedback loop that constrains circulating nutrient concentrations.  It also has many other functions that are tissue-specific.

Insulin resistance is a state in which cells lose sensitivity to the effects of insulin, eventually leading to a diminished ability to control circulating nutrients (glucose and fatty acids).  It is a major contributor to diabetes risk, and probably a contributor to the risk of cardiovascular disease, certain cancers and a number of other disorders. 

Why is it important to manage the concentration of circulating nutrients to keep them within a narrow range?  The answer to that question is the crux of this post. 

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Does High Circulating Insulin Drive Body Fat Accumulation? Answers from Genetically Modified Mice

The house mouse Mus musculus is an incredible research tool in the biomedical sciences, due to its ease of care and its ability to be genetically manipulated.  Although mice aren't humans, they resemble us closely in many ways, including how insulin signaling works.  Genetic manipulation of mice allows researchers to identify biological mechanisms and cause-effect relationships in a very precise manner.  One way of doing this is to create "knockout" mice that lack a specific gene, in an attempt to determine that gene's importance in a particular process.  Another way is to create transgenic mice that express a gene of interest, often modified in some way.  A third method is to use an extraordinary (but now common) tool called "Cre-lox" recombination (1), which allows us to delete or add a single gene in a specific tissue or cell type. 

Studying the relationship between obesity and insulin resistance is challenging, because the two typically travel together, confounding efforts to determine which is the cause and which is the effect of the other (or neither).  Some have proposed the hypothesis that high levels of circulating insulin promote body fat accumulation*.  To truly address this question, we need to consider targeted experiments that increase circulating insulin over long periods of time without altering a number of other factors throughout the body.  This is where mice come in.  Scientists are able to perform precise genetic interventions in mice that increase circulating insulin over a long period of time.  These mice should gain fat mass if the hypothesis is correct. 

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The Case for the Food Reward Hypothesis of Obesity, Part II

In this post, I'll explore whether or not the scientific evidence is consistent with the predictions of the food reward hypothesis, as outlined in the last post.

Before diving in, I'd like to address the critique that the food reward concept is a tautology or relies on circular reasoning (or is not testable/falsifiable).  This critique has no logical basis.  The reward and palatability value of a food is not defined by its effect on energy intake or body fatness.  In the research setting, food reward is measured by the ability of food or food-related stimuli to reinforce or motivate behavior (e.g., 1).  In humans, palatability is measured by having a person taste a food and rate its pleasantness in a standardized, quantifiable manner, or sometimes by looking at brain activity by fMRI or related techniques (2).  In rodents, it is measured by observing stereotyped facial responses to palatable and unpalatable foods, which are similar to those seen in human infants.  It is not a tautology or circular reasoning to say that the reinforcing value or pleasantness of food influences food intake and body fatness. These are quantifiable concepts and as I will explain, their relationship with food intake and body fatness can be, and already has been, tested in a controlled manner. 

1.   Increasing the reward/palatability value of the diet should cause fat gain in animals and humans

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A Roadmap to Obesity

In this post, I'll explain my current understanding of the factors that promote obesity in humans.  

Heritability

To a large degree, obesity is a heritable condition.  Various studies indicate that roughly two-thirds of the differences in body fatness between individuals is explained by heredity*, although estimates vary greatly (1).  However, we also know that obesity is not genetically determined, because in the US, the obesity rate has more than doubled in the last 30 years, consistent with what has happened to many other cultures (2).  How do we reconcile these two facts?  By understanding that genetic variability determines the degree of susceptibility to obesity-promoting factors.  In other words, in a natural environment with a natural diet, nearly everyone would be relatively lean, but when obesity-promoting factors are introduced, genetic makeup determines how resistant each person will be to fat gain.  As with the diseases of civilization, obesity is caused by a mismatch between our genetic heritage and our current environment.  This idea received experimental support from an interesting recent study (3).

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Obesity and the Brain

Nature Genetics just published a paper that caught my interest (1). Investigators reviewed the studies that have attempted to determine associations between genetic variants and common obesity (as judged by body mass index or BMI). In other words, they looked for "genes" that are suspected to make people fat.

There are a number of gene variants that associate with an increased or decreased risk of obesity. These fall into two categories: rare single-gene mutations that cause dramatic obesity, and common variants that are estimated to have a very small impact on body fatness. The former category cannot account for common obesity because it is far too rare, and the latter probably cannot account for it either because it has too little impact*. Genetics can't explain the fact that there were half as many obese people in the US 40 years ago. Here's a wise quote from the obesity researcher Dr. David L. Katz, quoted from an interview about the study (2):

Let us by all means study our genes, and their associations with our various shapes and sizes... But let's not let it distract us from the fact that our genes have not changed to account for the modern advent of epidemic obesity -- our environments and lifestyles have.

Exactly. So I don't usually pay much attention to "obesity genes", although I do think genetics contributes to how a body reacts to an unnatural diet/lifestyle. However, the first part of his statement is important too. Studying these types of associations can give us insights into the biological mechanisms of obesity when we ask the question "what do these genes do?" The processes these genes participate in should be the same processes that are most important in regulating fat mass.

So, what do the genes do? Of those that have a known function, nearly all of them act in the brain, and most act in known body fat regulation circuits in the hypothalamus (a brain region). The brain is the master regulator of body fat mass. It's also the master regulator of nearly all large-scale homeostatic systems in the body, including the endocrine (hormone) system. Now you know why I study the neurobiology of obesity.


* The authors estimated that "together, the 32 confirmed BMI loci explained 1.45% of the inter-individual variation in BMI." In other words, even if you were unlucky enough to inherit the 'fat' version of all 32 genes, which is exceedingly unlikely, you would only have a slightly higher risk of obesity than the general population.