212 - The Neuroscience of Obesity | Peter Attia, M.D. & Stephan Guyenet, Ph.D.

KEYPOINTS

• 01

  Obesity rose slowly for decades, then took off around 1980

  Stephan Guyenet, a neuroscientist and author of The Hungry Brain, says the earliest useful US data come from Civil War veterans measured around 1890–1900, when only a small fraction had a BMI over 30. Representative national sampling began in the 1960s, when about 12% of adults were obese. That rose to about 15% by the late 1970s and early 1980s and is about 43% today. Guyenet thinks the lifetime risk of obesity is well over 50% for US adults. Type 2 diabetes prevalence has risen roughly five-fold over the past 50 years.

• 02

  The 'obesity paradox' is mostly an artifact of illness causing weight loss

  Studies associated with Katherine Flegal found that the lowest mortality in meta-analyses of millions of people often fell in the overweight range. Yet excess fat drives diabetes, cardiovascular disease and some cancers. Guyenet says later research suggests the paradox comes mainly from reverse causation. Poorly controlled diabetes, kidney failure, COPD and cognitive decline all cause weight loss, which makes leanness look worse than it is.

• 03

  The hypothalamus regulates body fat like a thermostat

  Guyenet calls this regulatory system the 'lipostat'. The first clue came in 1840, when the Viennese physician Bernhard Mohr described a woman with rapid, extreme obesity who turned out at autopsy to have a tumour in her hypothalamus. Hypothalamic obesity from tumours or brain damage still occurs.

• 04

  Leptin defends against starvation more than against weight gain

  Leptin was discovered in 1994 by teams led by Jeffrey Friedman and Rudy Leibel as the missing gene in the extremely obese ob/ob mouse. Cutting calories by about 25% for a couple of days drops leptin far more than fat mass changes, and the brain reads that as a threat. Leptin resistance means higher leptin levels don't produce the expected reduction in appetite. The system is quite happy to let us gain weight. What it is built to prevent is starving.

• 05

  Body weight is highly heritable, and the genes act mostly in the brain

  Guyenet cites a meta-analysis of twin studies estimating BMI heritability at about 75%. Studies of about 800,000 people have found about 900 variants, each of small effect, and they are disproportionately expressed in the brain. Our genes haven't changed in 100 years, so the susceptibility was always there. What changed is the environment, which now matches it.

• 06

  Highly rewarding foods recalibrate the brain's reward system

  In Michael Krashes's mouse study, mice normally ate unrefined pellets. Once given calorie-dense, refined, high-fat pellets, their reward circuits devalued the old food, so it no longer satisfied or motivated them. Guyenet thinks the same happens to people raised around modern food. Gut neuropod cells, discovered around 2018, sense glucose, amino acids and fatty acids and signal directly to vagal neurons, which helps explain how strongly this learning is hardwired.

• 07

  The carbohydrate–insulin model versus energy balance

  The modern carbohydrate–insulin model, set out in a recent review led by David Ludwig, is far more complex than earlier versions. Guyenet and Kevin Hall represent the energy-balance view, which nearly all researchers studying body-fat regulation accept. A key piece of evidence is John Speakman's study of 29 diets in five mouse strains. Replacing carbohydrate with fat made mice fatter until fat reached about 60% of calories, and beyond that they got slimmer again. The combination of fat and carbohydrate seems most fattening, which is why both low-fat and low-carb diets can work.

• 08

  Work with the non-conscious brain, not against it

  Rather than relying on constant willpower, Guyenet suggests sending the brain signals that point toward slimming. Shape your food environment: keep tempting food out of sight and add effort barriers, since peeling an orange in another room beats grabbing chips. Choose foods that satisfy on fewer calories, and avoid liquid calories, which bypass the feedback system.

• 09

  Medication is now a reasonable option for people with obesity

  For a BMI of about 30–35 or higher with impaired quality of life or health concerns, Guyenet thinks medical treatment is worth considering and recommends seeing an obesity medicine specialist. He calls semaglutide, as far as can be told, very safe, with about 18% weight loss, more than diet and lifestyle typically achieve. Like lifestyle change, it has to be maintained. He says we are entering an era of drugs designed from mechanism rather than found by accident.