Does "Metabolically Healthy Obesity" Exist?

Obesity is strongly associated with metabolic alterations and negative health outcomes including diabetes, cardiovascular disease, and some types of cancer (1, 2, 3, 4).  Excess body fat is one of the primary causes of preventable health problems and mortality in the United States and many other affluent nations, ranking in importance with cigarette smoking and physical inactivity.  Obesity is thought to contribute to disease via the metabolic disturbances it causes, including excess glucose and lipids in the circulation, dysregulated hormone activity including insulin and leptin, and inflammatory effects.  This immediately raises two questions:

1. Does metabolically healthy obesity exist?
2. If so, are metabolically healthy obese people at an elevated risk of disease and death?

Does metabolically healthy obesity exist?

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Recent and Upcoming Appearances

Smarter Science of Slim

Jonathan Bailor recently released an interview we did a few months ago on the neurobiology of body fat regulation, and the implications for fat loss.  It's a good overview of the regulation of food intake and body fatness by the brain.  You can listen to it here.

Super Human Radio

Carl Lanore interviewed me about my lab's work on hypothalamic inflammation and obesity.  I'm currently wrapping up a postdoctoral fellowship with Dr. Michael Schwartz at the University of Washington, and the interview touches on our recent review paper "Hypothalamic Inflammation: Marker or Mechanism of Obesity Pathogenesis?"  Dan Pardi and I are frequent guests on Carl's show and I'm always impressed by how well Carl prepares prior to the interview.  You can listen to the interview here.

The Reality Check podcast

Pat Roach of the Reality Check podcast interviewed me about the scientific validity of the "carbohydrate-insulin hypothesis" of obesity.  The Reality Check podcast "explores a wide range of controversies and curiosities using science and critical thinking", and a dash of humor.  This one should be very informative for people who aren't sure what to believe and want a deeper perspective on the science of insulin and body weight regulation.  You can listen to it here.

Obesity Society conference

Next Thursday 11/9, I'll be speaking at the 2013 Obesity Society conference in Atlanta.  My talk is titled "The Glial Response to Obesity is Reversible", and it will be about my work on the reversibility of obesity-associated hypothalamic neuropathology in mice.  My talk will be part of the session "Neuronal Control of Satiety" between 3:00 and 4:30, specific time pending.  See you there!

Sleep and Genetic Obesity Risk

Evidence is steadily accumulating that insufficient sleep increases the risk of obesity and undermines fat loss efforts.  Short sleep duration is one of the most significant risk factors for obesity (1), and several potential mechanisms have been identified, including increased hunger, increased interest in calorie-dense highly palatable food, reduced drive to exercise, and alterations in hormones that influence appetite and body fatness.  Dan Pardi presented his research at AHS13 showing that sleep restriction reduces willpower to make healthy choices about food.

We also know that genetics has an outsized influence on obesity risk, accounting for about 70 percent of the variability in body fatness between people in affluent nations (2).  I have argued that "fat genes" don't directly lead to obesity, but they do determine who is susceptible to a fattening environment and who isn't (3).  I recently revisited a 2010 paper published in the journal Sleep by University of Washington researchers that supports this idea (4).

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Speaking in Lisbon on October 5

My friend Pedro Bastos graciously invited me to speak at a conference he organized in Lisbon on October 5 titled "Food, Nutrition and the Prevention of Chronic Diseases".  I will give two talks:

• "Ancestral Health: What is Our Human Potential?"  This talk will explore the health of non-industrial cultures in an effort to understand how much of our modern chronic disease burden is preventable, and it will briefly touch on one major aspect of non-industrial life that may protect against the "diseases of civilization".  This presentation will focus on age-adjusted data from high quality studies.  
• "Why Do We Overeat: a Neurobiological Perspective."  This talk will attempt to explain why most of us consume more calories than we need to maintain weight-- a phenomenon that is a central cause of morbidity and mortality in the modern world.  It will touch on some of the brain mechanisms involved in ingestive behavior, and outline a framework to explain why these mechanisms are often maladaptive in today's environment.

Pedro will speak about dairy consumption, vitamin D, and chronic disease.  

The conference is targeted to health professionals and students of nutrition, however it's open to anyone who is interested in these topics.  It's sponsored by NutriScience, a Portuguese nutrition education and consulting company.  Sadly, I don't speak Portuguese, so my talks will be in English.  

Access the full program, and register for the conference, using the links below:

Program

Registration

Is Refined Carbohydrate Addictive?

[Note: in previous versions, I mixed up "LGI" and "HGI" terms in a couple of spots.  These are now corrected.  Thanks to readers for pointing them out.]

Recently, a new study was published that triggered an avalanche of media reports suggesting that refined carbohydrate may be addictive:

Refined Carbs May Trigger Food Addiction
Refined Carbs May Trigger Food Addictions
Can You be Addicted to Carbs?
etc.

This makes for attention-grabbing headlines, but in fact the study had virtually nothing to do with food addiction.  The study made no attempt to measure addictive behavior related to refined carbohydrate or any other food, nor did it aim to do so.

So what did the study actually find, why is it being extrapolated to food addiction, and is this a reasonable extrapolation?  Answering these questions dredges up a number of interesting scientific points, some of which undermine popular notions of what determines eating behavior.

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More Thoughts on Cold Training: Biology Chimes In

Now that the concept of cold training for cold adaptation and fat loss has received scientific support, I've been thinking more about how to apply it.  A number of people have been practicing cold training for a long time, using various methods, most of which haven't been scientifically validated.  That doesn't mean the methods don't work (some of them probably do), but I don't know how far we can generalize individual results prior to seeing controlled studies.

The studies that were published two weeks ago used prolonged, mild cold exposure (60-63 F air) to achieve cold adaptation and fat loss (1, 2).  We still don't know whether or not we would see the same outcome from short, intense cold exposure such as a cold shower or brief cold water plunge.  Also, the fat loss that occurred was modest (5%), and the subjects started off lean rather than overweight.  Normally, overweight people lose more fat than lean people given the same fat loss intervention, but this possibility remains untested.  So the current research leaves a lot of stones unturned, some of which are directly relevant to popular cold training concepts.

In my last post on brown fat, I mentioned that we already know a lot about how brown fat activity is regulated, and I touched briefly on a few key points.  As is often the case, understanding the underlying biology provides clues that may help us train more effectively.  Let's see what the biology has to say.

Biology of Temperature Regulation

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AHS Talk This Saturday

For those who are attending the Ancestral Health Symposium this year, my talk will be at 9:00 AM on Saturday.  The title is "Insulin and Obesity: Reconciling Conflicting Evidence", and it will focus on the following two questions:

1. Does elevated insulin cause obesity; does obesity cause elevated insulin; or both?
2. Is there a unifying hypothesis that's able to explain all of the seemingly conflicting evidence cited by each side of the debate?

I'll approach the matter in true scientific fashion: stating hypotheses, making rational predictions based on those hypotheses, and seeing how well the evidence matches the predictions.  I'll explore the evidence in a way that has never been done before (to my knowledge), even on this blog.

Why am I giving this talk?  Two reasons.  First, it's an important question that has implications for the prevention and treatment of obesity, and it has received a lot of interest in the ancestral health community and to some extent among obesity researchers.  Second, I study the mechanisms of obesity professionally, I'm wrapping up a postdoc in a lab that has focused on the role of insulin in body fatness (lab of Dr. Michael W. Schwartz), and I've thought about this question a lot over the years-- so I'm in a good position to speak about it.

The talk will be accessible and informative to almost all knowledge levels, including researchers, physicians, and anyone who knows a little bit about insulin.  I'll cover most of the basics as we go.  I guarantee you'll learn something, whatever your knowledge level.

Brown Fat: It's a Big Deal

Non-shivering thermogenesis is the process by which the body generates extra heat without shivering.  Shivering is a way for the body to use muscular contractions to generate heat, but non-shivering thermogenesis uses a completely different mechanism to accomplish the same goal: a specialized fat-burning tissue called brown fat.  Brown fat is brown rather than white because it's packed with mitochondria, the power plants of the cell.  Under cold conditions, these mitochondria are activated, using a specialized molecular mechanism called uncoupling* to generate heat.

The mechanism of brown fat activation has been worked out fairly well in rodents, which rely heavily on non-shivering thermogenesis due to their small body size.  Specialized areas of the hypothalamus in the brain sense body temperature (through sensors in the brain and body), body energy status (by measuring leptin and satiety signals), stress level, and probably other factors, and integrate this information to set brown fat activity.  The hypothalamus does this by acting through the sympathetic nervous system, which heavily innervates brown fat.  As an aside, this process works basically the same in humans, as far as we currently know.  Those who claim that rodent models are irrelevant to humans are completely full of hot air**, as the high degree of conservation of the hypothalamus over 75 million years of evolution demonstrates.

Two new studies concurrently published in the Journal of Clinical Investigation last week demonstrate what I've suspected for a long time: brown fat can be 'trained' by cold exposure to be more active, and its activation by cold can reduce body fatness.

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The Genetics of Obesity, Part III

Genetics Loads the Gun, Environment Pulls the Trigger

Thanks to a WHS reader* for reminding me of the above quote by Dr. Francis Collins, director of the US National Institutes of Health**.  This is a concept that helps reconcile the following two seemingly contradictory observations:

1. Roughly 70 percent of obesity risk is genetically inherited, leaving only 30 percent of risk to environmental factors such as diet and lifestyle.
2. Diet and lifestyle have a large impact on obesity risk.  The prevalence of obesity has tripled in the last 30 years, and the prevalence of extreme obesity has increased by almost 10-fold.  This is presumably not enough time for genetic changes to account for it.

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The Genetics of Obesity, Part II

Rodents Lead the Way

The study of obesity genetics dates back more than half a century.  In 1949, researchers at the Jackson Laboratories identified a remarkably fat mouse, which they determined carried a spontaneous mutation in an unidentified gene.  They named this the "obese" (ob/ob) mouse.  Over the next few decades, researchers identified several other genetically obese mice with spontaneous mutations, including diabetic (db/db) mice, "agouti" (Avy) mice, and "Zucker" (fa/fa) rats.

At the time of discovery, no one knew where the mutations resided in the genome.  All they knew is that the mutations were in single genes, and they resulted in extreme obesity.  Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way.  Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators' pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned.  Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.

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The Genetics of Obesity, Part I

Choosing the Right Parents: the Best Way to Stay Lean?

In 1990, Dr. Claude Bouchard and colleagues published a simple but fascinating study demonstrating the importance of genetics in body fatness (1).  They took advantage of one of the most useful tools in human genetics: identical twins.  This is what happens when a single fertilized egg generates two embryos in utero and two genetically identical humans are born from the same womb.   By comparing identical twins to other people who are not genetically identical (e.g., non-identical twins), we can quantify the impact of genes vs. environment on individual characteristics (2).

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The Neurobiology of the Obesity Epidemic

I recently read an interesting review paper by Dr. Edmund T. Rolls titled "Taste, olfactory and food texture reward processing in the brain and the control of appetite" that I'll discuss in this post (1).  Dr. Rolls is a prolific neuroscience researcher at Oxford who focuses on "the brain mechanisms of perception, memory, emotion and feeding, and thus of perceptual, memory, emotional and appetite disorders."  His website is here.

The first half of the paper is technical and discusses some of Dr. Rolls' findings on how specific brain areas process sensory and reward information, and how individual neurons can integrate multiple sensory signals during this process.  I recommend reading it if you have the background and interest, but I'm not going to cover it here.  The second half of the paper is an attempt to explain the obesity epidemic based on what he knows about the brain and other aspects of human biology.

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Speaking at AHS13

The 2013 Ancestral Health Symposium will be held in Atlanta, GA, August 14-17.  Last year was a great conference, and I look forward to more informative talks and networking.  Tickets go fast, so reserve yours now if you plan to attend!

This year, I'll be speaking on insulin and obesity.  My talk will be titled "Insulin and Obesity: Reconciling Conflicting Evidence".  In this talk, I'll present the evidence for and against the idea that elevated insulin contributes to the development of obesity.  One hypothesis states that elevated insulin contributes to obesity, while the other states that elevated insulin is caused by obesity and does not contribute to it.  Both sides of the debate present evidence that appears compelling, and it often seems like each side is talking past the other rather than trying to incorporate all of the evidence into a larger, more powerful model.

There's a lot evidence that can be brought to bear on this question, but much of it hasn't reached the public yet.  I'll explore a broad swath of evidence from clinical case studies, observational studies, controlled trials, animal research, physiology, and cell biology to test the two competing hypotheses and outline a model that can explain all of the seemingly conflicting data.  Much of this information hasn't appeared on this blog.  My goal is to put together a talk that will be informative to a researcher but also accessible to an informed layperson.

On a separate note, my AHS12 talk "Digestive Health, Inflammation and the Metabolic Syndrome" has not been posted online because the video recording of my talk has mysteriously disappeared.  I think many WHS readers would be interested in the talk, since it covers research on the important and interdependent influence of gut health, inflammation, and psychological stress on the metabolic syndrome (the quintessential modern metabolic disorder).  I'm going to try to find time to make a narrated slideshow so I can post it on YouTube.

Food Variety, Calorie Intake, and Weight Gain

Let's kick off this post with a quote from a 2001 review paper (1):

Increased variety in the food supply may contribute to the development and maintenance of obesity.  Thirty-nine studies examining dietary variety, energy intake, and body composition are reviewed. Animal and human studies show that food consumption increases when there is more variety in a meal or diet and that greater dietary variety is associated with increased body weight and fat.

This may seem counterintuitive, since variety in the diet is generally seen as a good thing.  In some ways, it is a good thing, however in this post we'll see that it can have a downside.
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Book Review: Salt, Sugar, Fat

Michael Moss is a Pulitzer prize-winning journalist who has made a career writing about the US food system.  In his latest book, Salt, Sugar, Fat: How the Food Giants Hooked Us, he attempts to explain how the processed food industry has been so successful at increasing its control over US "stomach share".  Although the book doesn't focus on the obesity epidemic, the relevance is obvious.  Salt, Sugar, Fat is required reading for anyone who wants to understand why obesity is becoming more common in the US and throughout the world.

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Glucagon, Dietary Protein, and Low-Carbohydrate Diets

Glucagon is a hormone that plays an important role in blood glucose control.  Like insulin, it's secreted by the pancreas, though it's secreted by a different cell population than insulin (alpha vs. beta cells).  In some ways, glucagon opposes insulin.  However, the role of glucagon in metabolism is frequently misunderstood in diet-health circles.

The liver normally stores glucose in the form of glycogen and releases it into the bloodstream as needed.  It can also manufacture glucose from glycerol, lactate, and certain amino acids.  Glucagon's main job is to keep blood glucose from dipping too low by making sure the liver releases enough glucose.  There are a few situations where this is particularly important:

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Neuronal Control of Appetite, Metabolism and Weight

Last week, I attended a Keystone conference, "Neuronal Control of Appetite, Metabolism and Weight", in Banff.  Keystone conferences are small, focused meetings that tend to attract high quality science.  This particular conference centered around my own professional research interests, and it was incredibly informative.  This post is a summary of some of the most salient points.

Rapid Pace of Scientific Progress

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Body Fatness and Cardiovascular Risk Factors

I recently revisited a really cool paper published in the Lancet in 2009 on body fatness, biomarkers, health, and mortality (1). It's a meta-analysis that compiled body mass index (BMI) data from nearly 900,000 individual people, and related it to circulating lipids and various health outcomes.  This is one of the most authoritative papers on the subject.

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Why Do We Eat? A Neurobiological Perspective. Part VIII

In the (probably) last post of this series, I'll take the pieces that I've gradually outlined in previous posts, and put them together into a big-picture, common-sense framework for thinking about human eating behavior, and why we eat more today than ever before.

Why is Eating Behavior Regulated?

Let's start at the most fundamental level.  To be competitive in a natural environment, organisms must find rational ways of interacting with their surroundings to promote survival and reproduction.  One of the most important elements of survival is the acquisition of energy and chemical building blocks, either by photosynthesis, or (in the case of animals) eating other organisms.  This imperative drove the evolution of rational food seeking behaviors long before the emergence of humans, mammals, reptiles, amphibians, fish, worms, and even eukaryotes (organisms with nuclei).

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Why Do We Eat? A Neurobiological Perspective. Part VI

In previous posts in this series, I explained that the brain (primarily the mesolimbic system) integrates various factors to decide whether or not to drive food seeking and consumption behaviors.  These include homeostatic factors such as hunger, and non-homeostatic factors such as palatability and the social environment.

In this post, I'll examine the reward system more closely.  This is the system that governs the motivation for food, and behavioral reinforcement (a form of learning).  It does this by receiving information from other parts of the brain that it uses to determine if it's appropriate to drive (motivate) food seeking behavior.  I covered its role in motivation in the first post of the series, so in this post I'll address reinforcement.

Behavioral Reinforcement

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