Sunday, April 15, 2012


The thrifty gene hypothesis (feast and famine) suggests some people have thrifty genes that promote overeating and weight gain during times of plenty to prepare them for famines and that because famines no longer occur these people gain weight.
There are some problems with the thrifty gene hypothesis:
  • Hunter-gatherers maintain a stable and healthy body weight, despite rarely experiencing famines
  • During a famine, infectious disease and plant toxins kill more people than starvation
  • People can lose weight on ad libitum diets
  • Obese people use energy less efficiently
Calories in, calories out is true.  If you eat more calories than you expend you will gain weight and if you eat fewer calories than you expend you will lose weight.  But the real question is what makes some people overeat?
  • The low fat approach suggests fat causes obesity because fat has more calories per gram than carbs and protein, making it more energy dense
  • The low carb approach suggests carbohydrates cause obesity because carbohydrates increase insulin and insulin promotes fat storage
  • The low fructose approach suggests fructose is a toxin that is metabolised like alcohol, is converted to fat and causes obesity by firstly causing insulin resistance.
Yet people on both low fat and low carb diets spontaneously reduce their calories and lose more weight than those on calorie restricted diets.  Like CICO, the low fat argument doesn’t appreciate the role of satiety hormones and the low carb and low fructose mechanisms have counter evidence against them.  While the reasoning as to why these diets work is poor, it doesn’t mean they can’t be successful weight loss approaches.
Leptin is a hormone released by fat cells and communicates to the brain as to how much stored fat there is. The brain responds by adjusting appetite and energy expenditure to maintain a body fat setpoint. Leptin resistance is where the brain doesn’t receive as leptin and so thinks there’s less fat stored and compensates through something akin to the starvation response – increasing appetite and decreasing energy expenditure. Leptin resistance precedes and causes obesity. So what causes leptin resistance?
Inhibiting signal transduction and decreasing the number of hormone receptors are the major causes of hormone resistance. SOCS3 and PTP1B inhibit the signal transduction of leptin, causing leptin resistance.
Lipopolysaccharides >> Inflammation >> SOCS3 >> Leptin resistance
Mitochondrial dysfunction >> ER stress >> PTP1B >> Leptin resistance
Inflammation, mitochondrial dysfunction and ER stress can also cause the neurons that leptin signals to maintain weight neuron death to the neurons that receive leptin, which decreases the number of leptin receptors.
Some other causes of obesity include food reward, sleep loss and circadian rhythm disruption, and leptin transport.
Obesity is a complex disease, there are many factors that can contribute towards it.  There is no one cause of obesity just as there’s no one solution.
I prefer to look for problems in the homeostatic mechanisms that would ordinarily protect us from disease.  In the case of obesity that’s essentially leptin resistance.  Leptin resistance can be caused by elevated SOCS3 and PTP1B, which in turn are caused by inflammation and mitochondrial dysfunction/ER stress.  Inflammation and mitochondrial dysfunction/ER stress can also explain the strong associations between obesity and chronic disease.
Obesity isn’t a simple matter where discussions ending with calories in, calories out or feast and famine are helpful.  I consider obesity to be a symptom of an underlying pathology (inflammation, mitochondrial dysfunction, etc).  In my opinion, addressing the causes of obesity/weight gain is one of the few paths to sustainable weight loss/maintenance
Some Strategies for Obesity/Weight Loss/etc
This is for informational purposes only and is not meant to diagnose or treat any medical condition.
Improve Mitochondrial Function
See Mitochondrial Dysfunction (particularly the second half)
Reduce Inflammation
Reduce Food Reward
Improve Sleep


  1. I don't often share blog posts, but this one was an exception! Nice job!

  2. Hi Steven,

    I would challenge your conclusion based on my own experiences but I can't do it with so few characters you allow. I tried to find email for you but none. I am Paleo eater with AI and did the protocol and lost half of the obesity then plateaued. I also have a diabetic dog I learned a lot from too.