You are what you eat, or are you? The challenges of translating high-fat-fed rodents to human obesity and diabetes

Abstract: Obesity and type 2 diabetes mellitus (T2DM) are rapidly growing worldwide epidemics with major health consequences. Various human-based studies have confirmed that both genetic and environmental factors (particularly high-caloric diets and sedentary lifestyle) greatly contribute to human T2DM. Interactions between obesity, insulin resistance and β-cell dysfunction result in human T2DM, but the mechanisms regulating the interplay among these impairments remain unclear. Rodent models of high-fat diet (HFD)-induced obesity have been used widely to study human obesity and T2DM. With >9000 publications on PubMed over the past decade alone, many aspects of rodent T2DM have been elucidated; however, correlation to human obesity/diabetes remains poor. This review investigates the reasons for this translational discrepancy by critically evaluating rodent HFD models. Dietary modification in rodents appears to have limited translatable benefit for understanding and treating human obesity and diabetes due—at least in part—to divergent dietary compositions, species/strain and gender variability, inconsistent disease penetrance, severity and duration and lack of resemblance to human obesogenic pathophysiology. Therefore future research efforts dedicated to acquiring translationally relevant data—specifically human data, rather than findings based on rodent studies—would accelerate our understanding of disease mechanisms and development of therapeutics for human obesity/T2DM.

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Alex’s Notes: This review is an eye-opener. There are countless studies conducted with animal models, one of the most common being rodents, that many people including myself often translate to humans. It isn’t always intentional, but between reading the results and the authors conclusions we often forget that the subjects weren’t human! As the study authors point out,

“It appears that dietary modification in rodents has limited translatable benefit for understanding and treating human obesity and diabetes. The purpose of this review is to investigate the reasons for this translational discrepancy.”

The first major issue with rodent experiments is the type of diet they are on. Most researchers use commercially available and predefined high-fat diets (HFDs) that can range from 40-60% fat and include various combinations of saturated, monounsaturated, and polyunsaturated fatty acids. Moreover, the fat sources can vary widely and include ingredients such as butter, pork fat, beef tallow, lard and various oils such as corn, coconut, cottonseed, soybean, olive, peanut, sesame, cocoa butter and fish oils. The same holds true for high-carbohydrate diets rich in fructose or sucrose, and both high-carbohydrate and high-fat diets may be combined to induce metabolic pathologies. Put bluntly,

“Given the broad range of dietary modifications now utilized in obesity and T2DM research, it has not been possible to define the ‘ideal’ HFD nor generate a rodent model that can accurately mimic the human disease state.”

To put this in perspective, one study found weight gain to differ significantly between mice fed a HFD consisting of beef fat versus a HFD of canola oil (138% more weight gain with beef fat compared with canola oil) despite 40.8% of energy from fat in both diets. It has also been demonstrated that lard and olive oil cause higher insulin resistance in rodents than coconut or fish oil. This makes comparisons across studies… difficult to say the least.

Age is another factor to consider.Young mice (6-weeks old) are able to maintain normal blood glucose in response to a HFD by increasing β-cell mass and proliferation, whereas older mice (7–8-month old) were not able to counter-regulate by the same mechanism and became diabetic. Then of course depending on the species of the rodent used, the effects will be different. A study looking into this phenomenon found that HFD-induced weight gain ranged from 50% weight gain in Osborne-Mendel and Wistar-Lewis rats to 12% weight gain in S5B/P1 males to no weight gain in S5B/P1 females, indicating both strain- and sex-related differences.

You have the researchers themselves. Although this limitation (human experience/error with study protocols) applies to all studies, it is amplified in rodent models because of the reliance chemical, surgical, and genetic models of T2DM induction.

“In order for a rodent model to have relevance to human disease, it should effectively recapitulate the natural history, pathophysiology and complications in a manner similar to what is observed in humans.”

The above obviously isn’t the case, however, given that the typical Western diet is vastly different than the rodent diet. Moreover, our diets are much more complex than the carefully formulated rodent HFDs and we consume additional foodstuffs like alcohol that effect pathology but are not present in the rodent chow. Apart from the diet, our behavior is different as we have stress, emotions, and culture. We also consume our food during the day while rodents munch through the night. Most importantly,

“In humans, a complex genetic background interacts with environmental factors leading to progressive disease development, which occurs over a long period of time on the order of years to decades. In contrast, most rodent HFD studies last only a few weeks (and a few months at most) as rodents can develop obesity and insulin resistance after 2 weeks on a HFD, albeit to varying degrees. Because of rapid unnatural disease induction, HFD models often lack (or incorrectly mimic) T2DM-associated vascular complications, which develop over many years, usually starting long before the clinical diagnosis of overt hyperglycemia in humans.”

I hope you can see why this was an eye-opener. Quite honestly I will never again look at a rodent study the same way, and I will be far more critical of the procedures utilized. Understanding disease is paramount for developing treatments against them, but humans and the environment we live in cannot be recreated in a laboratory setting, let alone in another species. I will add that it is important to remember that this review focused on diabetes and obesity, and its information may not apply to other rodent applications such as that studying skeletal muscle physiology. However, healthy skepticism is still warranted.


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