Insulin sensitivity is preserved in mice made obese by feeding a high starch diet
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Evaluation Summary:
This study evaluates the effects of two distinct dietary methods that cause obesity in mice (high fat vs high starch) on insulin sensitivity and glucose homeostasis. Through a series of nicely performed physiology experiments, the authors demonstrated that high starch feeding causes obesity without deleterious effects on insulin sensitivity. This work will have an impact in the field and help define the important lipid mediators of metabolic disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Abstract
Obesity is generally associated with insulin resistance in liver and muscle and increased risk of developing type 2 diabetes, however there is a population of obese people that remain insulin sensitive. Similarly, recent work suggests that mice fed high carbohydrate diets can become obese without apparent glucose intolerance. To investigate this phenomenon further, we fed mice either a high fat (Hi-F) or high starch (Hi-ST) diet and measured adiposity, glucose tolerance, insulin sensitivity, and tissue lipids compared to control mice fed a standard laboratory chow. Both Hi-ST and Hi-F mice accumulated a similar amount of fat and tissue triglyceride compared to chow-fed mice. However, while Hi-F diet mice developed glucose intolerance as well as liver and muscle insulin resistance (assessed via euglycaemic/hyperinsulinaemic clamp), obese Hi-ST mice maintained glucose tolerance and insulin action similar to lean, chow-fed controls. This preservation of insulin action despite obesity in Hi-ST mice was associated with differences in de novo lipogenesis and levels of C22:0 ceramide in liver and C18:0 ceramide in muscle. This indicates that dietary manipulation can influence insulin action independently of the level of adiposity and that the presence of specific ceramide species correlates with these differences.
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Evaluation Summary:
This study evaluates the effects of two distinct dietary methods that cause obesity in mice (high fat vs high starch) on insulin sensitivity and glucose homeostasis. Through a series of nicely performed physiology experiments, the authors demonstrated that high starch feeding causes obesity without deleterious effects on insulin sensitivity. This work will have an impact in the field and help define the important lipid mediators of metabolic disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Obesity is considered a key risk factor in the development of insulin resistance, which is itself a key component of type 2 diabetes. As such, a common experimental practice to induce insulin resistance in rodents is to render them obese by feeding them a high-fat diet. However, there are certain individuals in the human population that are obese but do not present with insulin resistance (so-called "healthy obese"). The present studies sought to determine whether obesity per se is always associated with insulin resistance. To this end, the authors fed mice either a low-fat chow diet, a high-fat diet, or a high-starch diet. The high-fat and high-starch diets both promoted equivalent weight gain and obesity. As expected, the mice rendered obese by eating the high-fat diet were insulin resistant, as determined …
Reviewer #1 (Public Review):
Obesity is considered a key risk factor in the development of insulin resistance, which is itself a key component of type 2 diabetes. As such, a common experimental practice to induce insulin resistance in rodents is to render them obese by feeding them a high-fat diet. However, there are certain individuals in the human population that are obese but do not present with insulin resistance (so-called "healthy obese"). The present studies sought to determine whether obesity per se is always associated with insulin resistance. To this end, the authors fed mice either a low-fat chow diet, a high-fat diet, or a high-starch diet. The high-fat and high-starch diets both promoted equivalent weight gain and obesity. As expected, the mice rendered obese by eating the high-fat diet were insulin resistant, as determined by several experimental tests to assess insulin action. Surprisingly, the mice rendered obese by consuming the high-starch diet were not insulin resistant. When the authors measured a variety of factors in multiple tissues, they determined that mice fed a high-starch diet showed markers of the improved handling of carbohydrates, which likely explained why these mice did not display insulin resistance. These are important findings that provide nuance to the fields of obesity and diabetes by suggesting that not all forms of obesity are necessarily associated with insulin resistance. Furthermore, the molecular analyses conducted in these studies identify potential targets for improving the handling of carbohydrates in obese individuals.
The approaches used by the investigators were outstanding. Several different experimental tests were used to assess insulin action, including glucose and insulin tolerance tests, measurements of insulin signaling, and the hyperinsulinemic-euglycemic clamp. The conclusions are largely supported by the results obtained. One minor weakness is that these studies are largely observational in that they show correlations between obesity, degrees of insulin resistance, and changes in specific genes/proteins and/or metabolites, but they do not necessarily show causation. This is considered a minor weakness since the goal of the study was not to show causation but instead to test whether obesity is always associated with insulin resistance.
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Reviewer #2 (Public Review):
In this manuscript by Brandon et al, the investigators compared two obesity-causing diets in mice (high-fat vs high-starch) and defined their ability to cause insulin resistance and glucose intolerance in mice. In response to weeks of diet feeding, both diets led to the predicted increase in body weight and adipose tissue mass. However, feeding high starch did not lead to abnormalities in glucose tolerance or insulin sensitivity as documented by hyperinsulinemic-euglycemic clamp studies. However, a high-fat diet led to the predicted (and published) abnormalities in glucose tolerance and insulin resistance, particularly at the level of the liver, brown adipose tissue, and skeletal muscle. Notably, these abnormalities were not due to defects in canonical insulin signaling intermediates such as AKT. …
Reviewer #2 (Public Review):
In this manuscript by Brandon et al, the investigators compared two obesity-causing diets in mice (high-fat vs high-starch) and defined their ability to cause insulin resistance and glucose intolerance in mice. In response to weeks of diet feeding, both diets led to the predicted increase in body weight and adipose tissue mass. However, feeding high starch did not lead to abnormalities in glucose tolerance or insulin sensitivity as documented by hyperinsulinemic-euglycemic clamp studies. However, a high-fat diet led to the predicted (and published) abnormalities in glucose tolerance and insulin resistance, particularly at the level of the liver, brown adipose tissue, and skeletal muscle. Notably, these abnormalities were not due to defects in canonical insulin signaling intermediates such as AKT. Mechanistically, the authors performed lipidomics and suggest changes in particular ceramide species that are hypothesized to contribute to these deleterious effects on metabolism.
The major strengths of this manuscript are the nicely designed, rigorous, and well-executed experiments that directly compare two diet models and the use of elegant physiology experiments like clamp studies. These are important benchmark studies and will have a high impact in the field. Signaling, lipidomics, and clamp studies are all well-executed and are complementary to each other. A weakness of the current manuscript is the limited exploration of the white adipose tissue in both models. It is unclear if there is altered insulin signaling in white adipose tissue and changes in lipolysis that drive insulin resistance in the high-fat diet model. This would be predicted based on the literature and the inclusion of these data would help support the overall conclusions of this manuscript and its impact in the field.
Another weakness is that the causal role of the implicated ceramide species is not yet defined. However, in my opinion, this is beyond the scope of this manuscript as these studies will form the foundation of future experiments to directly evaluate/validate the specific role of ceramide in the high-fat diet effect. This is particularly important given that no changes were observed in canonical insulin signaling as predicted by the literature.
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Reviewer #3 (Public Review):
The authors nicely demonstrate tissue-specific differences in lipogenesis and insulin sensitivity which are differentially regulated in a diet-dependent manner. With the addition of comprehensive lipidomic phenotyping, their data implicate the differential regulation of ceramide accumulation as a likely mediator of insulin resistance in muscle and liver. Studies of dietary regulation of metabolic dysfunction, like this, are essential for understanding the etiology of metabolic diseases and efforts to combat them. With the exhaustive metabolic and lipidomic analyses, this paper can be a great resource for the field.
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