I’d like to get some issues off my chest and take you along the journey I have been traveling recently.
When I first started writing for ketopia, I noticed in the journals a large amount of articles pointing to high fat diets as the end-all and be-all of obesity. There are endless articles about this:
- High-fat Diets: Modeling the Metabolic Disorders of Human Obesity in Rodents
- Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice.
- Effect of age, sex, and site on the cellularity of the adipose tissue in mice and rats rendered obese by a high-fat diet
- The High-Fat Diet–Fed Mouse: A Model for Studying Mechanisms and Treatment of Impaired Glucose Tolerance and Type 2 Diabetes
Now as you may infer, I’m a fan of the ketogenic diet, and thus was surprised and a bit distraught at the amount of literature stating that high fat diets can make a healthy mouse into an obese, type 2 diabetes mouse so rapidly. At this point I let my bias get the best of me and started believing that mice are not good model organisms for obesity research.
If you look through my previous articles you may notice the distinct absence of pure mouse research articles. I even found other people who believed the same thing as I did. Mice are terrible model organisms for obesity! Why do scientists still adhere to this obvious flawed model?! This is outrageous!
I searched endlessly for articles to support my belief. When I ran into this article (Assessment of Diet-induced Obese Rats as an Obesity Model by Comparative Functional Genomics) I started my flailing downward spiral. See this paragraph:
Our study based on gene-expression profiling suggested that DIO rats in general represent an appropriate obesity model. However, the discrepancies in gene-expression alterations between DIO rats and obese humans, particularly in the metabolic pathways, may explain the limitations of using DIO rodent models in obesity research and drug discovery.
Oh how I CLUNG to the “However”! It was shameful, and saddening. How much denial I fell into about this one article! Maybe particular metabolic pathways do account for all the differences… It has to be. Right? Right….?
At some point, unwilling to admit defeat, I started researching mice on low carbohydrate diets. I found this article (Very Low-Carbohydrate versus Isocaloric High-Carbohydrate Diet in Dietary Obese Rats) and was thrust even further into denial:
In summary, when energy intake was matched, the VLC-HF diet provided no advantage over the HC-LF diet in loss of body fat, decrease in plasma cholesterol levels, improvement in fasting or post-load insulin resistance, or restoration of glycemic control in dietary obese rats. These results underscore the need for strict control of energy intake in studies of the effects of VLC diets on obesity and the metabolic syndrome. Although rats on the VLC-HF diet did show lower plasma triacylglycerol levels than did rats on the HC-LF diet by the end of Phase 2, this reduction was accompanied by retarded loss of hepatic, retroperitoneal, and total body fat mass. These latter findings support the view that a VLC-HF diet may promote storage of fat by the liver, visceral fat pads, and other sites as compared with an HC-LF diet.
There however was one paragraph that kept my irrational hope alive:
Energy restriction and not diet composition was responsible for the observed ketosis at the end of Phase 1 (Week 10) because equal numbers of rats on the VLC-HF and HC-LF diets showed elevated plasma β-hydroxybutyrate levels in the fed state. The failure of the VLC-HF1 diet to be more ketogenic than the HC-LF diet, which was equally hypocaloric but much higher in carbohydrate (5% vs. 60%), may be due to the high protein content of the VLC diet (35%, Table 1). In our pilot study (data not shown) and in other studies (18, 19), ketosis, along with marked hypophagia, was consistently produced using higher fat but much lower protein contents (5% to 13%). The results suggest that the dietary conditions needed to induce ketosis may differ between humans and rats.
So then, obviously, I eliminated any mention of “low carb” or “high fat”. It turns out that a rose by any other name does smell like a million other things if you’re searching for it through research journals…
We found that mice tolerated the KD well, consuming at least as many calories as mice fed a high-fat diet. However, mice eating KD failed to gain weight despite the high caloric density of the diet. Compared with mice fed standard chow, mice fed KD transiently lost weight and then stabilized at a lower weight than chow-fed animals in a pattern that was the same as that seen calorie-restricted mice. KD fed mice had a unique metabolic and physiological profile, exhibiting increased energy expenditure and very low respiratory quotient. Insulin levels were extremely low compared with both animals fed chow and animals fed high-fat diet. Furthermore, despite the consumption of saturated fat, serum lipids did not increase.
Do you smell that? It smells like roses.
So I had reached the end of my journey. From this article it clearly stated that the high fat diet often used in mice obesity studies was also high in carbohydrates, the ketogenic diet failed to induce obesity and was also capable of reversing diet induced obesity, and the energy balance in animals on the ketogenic diet was controlled by mechanisms outside of normal hypothalamic pathways. In contrast to caloric restricted animals, where testosterone levels dropped 30%, ketogenic animals maintained normal testosterone levels and females continued to cycle normally. There was also no evidence of muscle wasting despite lowered protein intake- showing ketogenic diets to be protein sparing.
Also look at that proper scientific diagram. LOOK AT IT. (I’m talking to you, Phinney and Volek!)
So this is the end of my journey. Mice are, in fact, proper model organisms for obesity research. My fatal flaw was not inspecting the methods carefully enough. “High fat” diets actually meant high fat with high sugar. “Very low carbohydrate” was low carb but high protein– which may work okay in humans, but does not in mice. This is the biggest difference between mice and men. To study a pure ketogenic diet we must tailor the diet for the creature. Mice have a lower protein requirement than humans, so lowering protein for mice lowers body weight but not lean mass whereas raising protein intake for humans is associated with better weight maintenance (see A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations).
So I’m sorry, scientists. I know mouse research sucks (they’re mean little bastards), but it looks like they’re going to stay around for a while longer in obesity research.
- A high-fat, ketogenic diet induces a unique metabolic state in mice, Kennedy, Pissios, et al. American Journal of Physiology – Endocrinology and Metabolism, June 2007 vol. 292 no. 6 E1724-E1739.
- A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations, Weigle, Breen, Matthys et al. American Journal of Clinical Nutrition, July 2005 vol. 82 no. 1 41-48.
- Assessment of Diet-induced Obese Rats as an Obesity Model by Comparative Functional Genomics, Li, Zhang, Hu et al. Obesity, 2008, 16: 811–818. doi: 10.1038/oby.2007.116.
- Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice, Lin, Thomas, et al. International Journal of Obesity (2000), Volume 24, Number 5, Pages 639-646.
- Effect of age, sex, and site on the cellularity of the adipose tissue in mice and rats rendered obese by a high-fat diet, Daniel Lemmonier, The Journal of Clinical Investigation. 1972 November; 51(11): 2907–2915. doi: 10.1172/JCI107115.
- High-fat Diets: Modeling the Metabolic Disorders of Human Obesity in Rodents, Buettner, Schölmerich, and Bollheimer. Obesity, 15: 798–808. doi: 10.1038/oby.2007.608.
- The High-Fat Diet–Fed Mouse: A Model for Studying Mechanisms and Treatment of Impaired Glucose Tolerance and Type 2 Diabetes, Winzel and Ahrén. Diabetes, December 2004 vol. 53 no. suppl 3 S215-S219.
- Very Low-Carbohydrate versus Isocaloric High-Carbohydrate Diet in Dietary Obese Rats, Axen and Axen. 2006, Very Low-Carbohydrate versus Isocaloric High-Carbohydrate Diet in Dietary Obese Rats. Obesity, 14: 1344–1352. doi: 10.1038/oby.2006.152