This One Trick Can Prevent Obesity! Quick Study Analysis

tl;dr: Imagine if you're in the business of obesity and suddenly you can't make obesity happen.

I’m going to do a bit of conflating here. Type 2 diabetes mellitus (T2DM) and obesity often (but not always) happen together—even in people who come down with T2DM, they often have visceral adiposity (think pot belly) even if they don’t have what we think of as obesity (Jung, 2016). So I’m going to treat them as aspects of one thing, for rhetorical purposes. They probably are just aspects of one thing, but as that’s not a universal opinion, I wanted to make it clear.

The Obesity Industry

Surprisingly, there’s a whole industry geared at producing obesity.

Obesity has become pandemic, and along with the many industries this has spawned, both medical (‘treatments’) and otherwise (larger clothes?), there is an entire industry geared to studying what causes obesity, and how to… cure it?

“Obesity is now a global pandemic, but there is little consensus about the causes.” (Speakman, 2023)

There are hordes of obesity researchers, who, for the last “fifty years” (Speakman, 2023) have been diligently studying what causes obesity and what to do about it.

The conclusion, in the sometimes humorous conclusion to many a research paper in many a field of research, is “more study required”.

“By building on the considerable advances made in the past 50 years, the study of the causes of obesity promises to be a rich area for discovery that may be transformative for the lives of millions of people. Improving our understanding of environmental drivers and how these interact with genetic composition is vital to making future inroads to this serious medical condition.” (Speakman, 2023)

And then there is the obesity industry. This is the group of companies that provide the resources needed by these researchers to study obesity. You see, you can’t study obesity if you don’t have obesity. Since it can’t be done in humans, for a variety of reasons too obvious to elucidate here, most obesity researchers rely on rodents.

Unfortunately, rodents tend not to get fat, so researchers rely on mutant rodents, those with a mutation that causes them to get fat, sometimes spontaneously, often only when fed a specific diet. There are companies that do little else but raise these mice and deliver them, ready to be plumped up, or even—it’s a service industry!—pre-plumped. Jackson Laboratory leads the field.

Jackson Lab, mouse central.

There are also companies that produce the diets that make these rodents obese. I posted recently about the 25th anniversary of the most successful diet-induced obesity (DIO) diet, in the context of how different diets induce obesity:

Poll Results: Which Diet Is Most Obesogenic?

That company is Research Diets (RD), and their “gold standard” DIO diet is called D12492 (Yeung, 2024). (75% of respondents got the wrong answer in that poll, by the way.) In many rodent models, D12492 will also produce T2DM.

“The C57BL/6 mouse strain has been shown to become obese, insulin resistant and glucose intolerant in response to consumption of a high (58%–60%) fat diet and is the most-used model for studying diet induced obesity and its co-morbidities [7,8].”

HFD = D12492 (Omar, 2012, Figure 1C)

In the very best manner of Capitalism, the obesity industry is very good at producing animals and diets that reliably produce obesity. Really they must, after all, that’s what they are paid to do.

If you were an obesity researcher, would you buy animals or diets that don’t reliably produce obesity? Replication is the essence of science, and the obesity industry has the replication of the induction of obesity down to a science.

But Sometimes Something Goes Wrong

One of the rodent models is called the Zucker Diabetic Fatty rat, or ZDF.

If you would like a cute, but fat and sick, rat, Charles River will sell you a ZDF!

In 1974 or so, a mutation occurred in the rats at the pharmaceutical company Eli Lilly that led to the male rats consistently getting obese and T2DM on the regular diet (Purina 5008) fed to the rats. These rats are now maintained by the Charles River (CR) company.

“The obese male ZDF rat plays a pivotal role in studying the cascade of physiologic events associated with the onset and treatment of T2D. The female ZDF can also be used as a model for T2D, but unlike the male, the female requires dietary modification to induce the diabetic state.” (Mulder, 2010)

Many researchers use only the female rats, since this is a more realistic model of human disease. Unusually for these sorts of animals, CR is quite specific about what to feed these rats to induce disease. You had to use the RD C13004 diet.

“Although older studies documented that obese female ZDF rats became diabetic when fed RD C13004, beginning in 2007, Charles River received several reports from researchers that these rats no longer developed diabetes when placed on this diet.” (Mulder, 2010)

If you are buying a rat that is basically guaranteed to produce obesity and diabetes, this is a catastrophe. How are you going to publish a paper to show that you are still working on the “what causes obesity” problem, if your rats won’t become obese?!

And obviously, it’s also a problem for CR.

Engineering Obesity

When the model was first discovered, it was not immediately obvious what would cause the female rats to get sick.

“The obese ZDF female does not become reliably diabetic on standard chow diets. Initially, attempts to induce diabetes in females were frustrating. They included ovariectomy and feeding a variety of chow diets. The sex-hormone modulation by ovariectomy did not result in diabetes. However, a small number of the obese females became diabetic on Purina chow #5015. Over time, a number of other synthetic diets were developed and tested. Feeding these diets to obese female ZDF rats did not result in producing diabetes. However, since some obese females did get diabetic on 5015, the formulation was closely examined and was found to have a fairly unique ingredient that contained high levels of pork fat. This discovery led to the addition of more of this product (30% by weight) to the 5015 formulation. This diet became identified as C13004 (research diets).” (Shafrir, 2007)

That “fairly unique ingredient” is “Ho-Milc”. What on Earth is that?

(Ulman, 1996)

One infers from the above that Ho-Milc contains “high levels of pork fat”. It turns out that Ho-Milc is a milk “replacer”: “Ho-Milc fat product containing 60% animal fat and 7% milk protein, Merrick Foods, Inc., Union Center, WI” (Seegrabber, 1986: This is worth a post all on its own!). Specifically, an “Animal and/or Vegetable Based Milk Substitute in Powdered Form” (Kattman, 1981). Ho-Milc must be the marketing department’s contraction of Whole Milk—it is not whole milk, of course.

Sadly, Merrick sold their milk replacer business to what is now called Actus Nutrition, and I can’t find any further information online.

So we don’t know what changed in Ho-Milc in 2007 that made it suddenly stop making female ZDF rats diabetic. But we can guess. They discontinued using pork fat. I wish we knew what they replaced it with…

“Subsequently, Charles River learned that certain nutritional components of RD C13004 had been modified. After first ruling out environmental and genetic factors as possible causes of the loss of the diabetic phenotype, Charles River experimentally evaluated the RD C13004 diet and confirmed that it no longer reliably produced diabetes in the obese female. Subsequently, Charles River performed a series of studies that indicated that the semi-purified diet RD 12468 reliably produced a diabetic phenotype, indicated by hyperglycemia and insulinopenia, in the female ZDF rat.” (Mulder, 2010)

RD knows all about using lard for obesity research. D12492 was based on an older, lower-fat diet called D12451.

“The genesis of D12492 traces back to its predecessor, D12451, formulated in 1996 with a fat content of 45 kcal%. However, the scientific community needed a diet with even higher fat in the hope of accelerating and intensifying the onset of the obesity phenotype…” (Mulder, 2010)

D12451 has too much sugar and carbohydrate, so those ingredients were replaced with more lard.

“This involved trying several sources of fat as well as developing new production processes.”

(Mulder, 2010)

They say that engineering is applied science. RD has got obesity science down to an engineering problem.

“In the end, lard was included as the main source of fat due to the consistency of its fatty acid profile and its physical characteristics that allow the diet to be produced in pellet form.” (Mulder, 2010)

One can imagine RD’s response to CR’s panicked phone call about the C13004 diet not working any more: “Oh, we know what to do…”

Charles River recommends that investigators consider utilizing RD 12468 to reliably induce a diabetic phenotype in the female ZDF rat.

“Alternatively, Charles River can provide preconditioned female ZDF rats fed RD 12468 upon request.” (Mulder, 2010)

D12468 replaced C13004. It no longer includes Purina #5015 (so probably more profitable for RD), but it has lard.

Genetics Is Destiny, Diet Is Not

Both the male and females ZDF rats are doomed to obesity. They are missing their functional leptin receptor due to a genetic mutation, and thus their brains cannot receive the signal to stop eating for which leptin is the messenger (Shafrir, 2007).

The males, similarly, are doomed to diabetes, but the females are not.

Most DIO rodent models are not doomed to obesity. The researchers go through the exercise of feeding them an obesogenic diet, and then doing whatever it is they would like to do to get another paper published.

What this little episode demonstrates is how quickly industry can figure out what is causing/not causing obesity and diabetes. When their money is on the line, they can figure it out in short order.

For more on what ingredient in D12492 (and D12468) causes obesity:

Does Linoleic Acid Induce Obesity? Part 1

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References

Jung, S. H., Ha, K. H., & Kim, D. J. (2016). Visceral Fat Mass Has Stronger Associations with Diabetes and Prediabetes than Other Anthropometric Obesity Indicators among Korean Adults. Yonsei Medical Journal, 57(3), 674–680. https://doi.org/10.3349/ymj.2016.57.3.674

Kattman, D. E. (1981, October 20). HO-MILC Trademark of MERRICK’S, INC. - Registration Number 1186016—Serial Number 73185763 :: [Informational]. Justia Trademarks. http://trademarks.justia.com/731/85/ho-73185763.html

Mulder, G., Luo, S., & Gramlich, P. (2010). Zucker Diabetic Fatty (ZDF) Rat (Obese fa/fa). Charles River. Retrieved April 21, 2025, from https://www.criver.com/products-services/find-model/zdf-rat-obese

Omar, B., Pacini, G., & Ahrén, B. (2012). Differential Development of Glucose Intolerance and Pancreatic Islet Adaptation in Multiple Diet Induced Obesity Models. Nutrients, 4(10), Article 10. https://doi.org/10.3390/nu4101367

Seegraber, F. J., & Morrill, J. L. (1986). Effect of Protein Source in Calf Milk Replacers on Morphology and Absorptive Ability of Small Intestine1. Journal of Dairy Science, 69(2), 460–469. https://doi.org/10.3168/jds.S0022-0302(86)80424-6

Shafrir, E. (Ed.). (2007). Chapter 4: The Zucker Diabetic Fatty (ZDF) Rat—Lessons from a Leptin Receptor Defect Diabetic Model. In Animal Models of Diabetes, Second Edition: Frontiers in Research (2nd ed, pp. 103–118). Taylor and Francis.

Speakman, J. R., Sørensen, T. I. A., Hall, K. D., & Allison, D. B. (2023). Unanswered Questions About the Causes of Obesity. Science, 381(6661), 944–946. https://doi.org/10.1126/science.adg2718

Ulman, E. A. (1996, October 8). C13004 Formula [Advertisement]. Research Diets, Inc. http://67.20.83.195/china/pdf/formulas/C13004.pdf

Yeung, S. (2024, March 18). Unveiling the Legacy: The Formulation of the 60 kcal% Fat Diet by Research Diets Inc. 25 Years Ago—Research Diets, Inc. [Advertisement]. Research Diets, Inc. https://researchdiets.com/blog/posts/unveiling-the-legacy-the-formulation-of-the-60-kcal-fat-diet-by-research-diets-inc-25-years-ago