Understanding diet-induced obesity

It has been discovered that the development of insulin resistance and Type 2 diabetes in obese patients is an individual occurrence; the CNM Group searches to find out why

Ulf Risérus and his researchers in the Clinical and Nutrition Metabolism Group (CNM) at Uppsala University are trying to find out why some obese individuals, but not others, develop insulin resistance and Type 2 diabetes in response to a high-calorie diet. Although genetics, gender and physical activity play their roles, the composition of the diet might prove to be a very important modifiable determinant of body composition and metabolic response to high-calorie diets.

Risérus’ group recently showed that some adverse cardiovascular effects of weight gain can be prevented by increasing the amount of unsaturated fats and decreasing saturated fats in the diet. It appears that different fatty acids in combination with sugars have divergent effects on abdominal body fat accumulation and muscle mass gain. It is now of major importance to understand in more detail how abdominal and liver fat deposition from high-energy diets is influenced by dietary composition. The CNM is particularly interested in dietary fatty acids, but also other key nutrients (e.g. carbohydrates, sugars and amino acids) that may interact with fatty acids in handling excess energy and influence body fat accumulation, metabolic disorders, and subsequently obesity-related diseases (Fig. 1). Some of the key research topics of the CNM are listed below.

  • Dietary regulation of ectopic fat accumulation, insulin resistance and Type 2 diabetes;
  • Role of fatty acid composition in modulating body composition (fat and lean tissue);
  • Use of dietary biomarkers for understanding dietary impact on obesity-related diseases;
  • Role of dietary fatty acids and fatty acid metabolism in cardiometabolic disease;
  • Role of a Nordic dietary pattern in the prevention of obesity-related diseases; and
  • Role of different dairy foods and their structural components in influencing disease risk.

Background

High-calorie diets and positive energy balance are key drivers of weight gain. Moderate weight gain, however, develops gradually over several years and decades in most populations, but the cardiometabolic consequences of such moderate weight gain are unclear. Although obesity is a global health problem, abdominal visceral obesity is a stronger predictor of premature death and cardiovascular disease than overall obesity (measured as BMI). In addition, excessive accumulation of fat in the liver has been closely linked to insulin resistance and elevated blood lipids, and proposed to be a causal factor of Type 2 diabetes. Visceral fat and liver fat are thus important targets in non-pharmacological and pharmacological strategies to prevent and treat obesity-related diseases. It has been hitherto unclear whether the effects of moderate weight gain on liver fat and body composition can be modified by dietary composition. Energy excess and sedentary lifestyles promote both overall and abdominal obesity, but we now have reason to believe that the composition of the diet partly determines whether being overweight will cause cardiometabolic health problems in the individual.

Ectopic fat and insulin resistance

Factors influencing body fat accumulation are poorly understood, and it is to a large extent unknown why some individuals accumulate ectopic fat, i.e. fat deposition in places other than subcutaneous adipose tissue – the liver, muscle, heart, pancreas and intra-abdominally. Furthermore, individuals that deposit ectopic fat during hypercaloric diets without increasing muscle mass may develop a ‘sarcopenic obese phenotype’ and are prone to develop insulin resistance and metabolic disease. Thus, whereas some obese individuals develop cardiometabolic diseases, others are surprisingly healthy throughout their lives. Such discrepancies may involve differences in body composition (ectopic fat deposition versus subcutaneous fat deposition), genetic factors, gender, physical activity and/or diet. Abdominal visceral obesity and excess liver fat have been especially linked to metabolic disorders, including elevated blood lipids, low-grade inflammation, insulin resistance and Type 2 diabetes. Non-alcoholic fatty liver disease (NAFLD) is a growing health problem, affecting as much as ~25% of western populations.

Diet could both cause and prevent diabetes

Diabetes is on the rise globally, and the dramatic increase in the disease is expected to cause major suffering and premature deaths in cardiovascular disease, as well as causing a high financial burden on our society. Diabetes is, however, highly preventable, and diet is key. In fact, without exposure of high-energy diets, Type 2 diabetes would not exist. Nonetheless, there are still major knowledge gaps in how to best prevent and treat Type 2 diabetes and its closely associated cardiovascular complications.

At CNM we investigate the link between diets and foods with development of Type 2 diabetes (Fig. 1). Among dietary components, fatty acids may play key roles in fat and glucose metabolism since they are not only carriers of energy but also signalling molecules and gene regulators, as well as altering the physical properties of cell membranes and thereby affecting membrane function in basically all cells of the body. Accumulating, but not conclusive, evidence indicates that partial replacement of saturated fats with polyunsaturated fats from non-hydrogenated vegetable oils (rich in omega-6 fatty acids) could improve insulin sensitivity and decrease risk of Type 2 diabetes.

Diet-induced weight gain and ectopic fat (LIPOGAIN study)

Research performed by the CNM has recently investigated the impact of different types of dietary fatty acids on body composition and ectopic fat accumulation. Specifically, our recent randomised intervention study (LIPOGAIN) suggests that excess saturated fat builds more ectopic fat and less muscle than polyunsaturated fat (Fig. 2). This is the first data in humans to show that the fat composition of foods not only influences cholesterol levels and the risk of cardiovascular disease but also determines where the fat will be stored in the body during a high-calorie diet. The findings have recently been published in two American journals (Rosqvist et al.: Diabetes and Iggman et al.: Journal of the American Heart Association). In the latter paper we also show that even a modest increase in bodyweight (less than 2kg) in lean and young individuals promotes signs of insulin resistance (by ~20%) as well as subclinical vascular endothelial dysfunction. Importantly, these adverse cardiometabolic effects of modest weight gain were partly outweighed if there was a high proportion of polyunsaturated fats (n-6 PUFA) in the hypercaloric diet, rather than a high proportion of saturated fats.

The LIPOGAIN study involved 39 young adult men and women of normal weight who ate 750 extra calories per day for seven weeks. The goal was to gain 3% of their starting weight. One half of the subjects were randomised to consume surplus calories from muffins baked on polyunsaturated fat (sunflower oil), while the other half got their surplus calories from muffins baked on saturated fat (palm oil). Both diets contained the same amount of sugar, carbohydrates, fat, cholesterol and protein; the only difference between muffins was the type of fat. The increase in body fat and the distribution of fat in the body were measured using magnetic resonance imaging (MRI scans) before and after the weight gain, as was the muscle mass in the body. Gene expression (mRNA) was measured in the abdominal fat before and after the weight gain with the help of a microarray gene chip that examines several thousand genes at a time.

Fatty acid-dependent effects on ectopic fat deposition

The LIPOGAIN study showed that despite comparable weight gain between the two diet groups, the surplus consumption of saturated fat diet caused a markedly greater increase in the amount of fat in the liver and abdomen (visceral fat) in comparison with the surplus consumption of polyunsaturated fat (Fig. 2). Moreover the total amount of body fat was greater in the saturated fat group, while, on the other hand, the increase in muscle mass was three times less for those who ate saturated fat compared with those who ate polyunsaturated fat (Fig. 2a). Thus, gaining weight on excess calories from polyunsaturated fat caused more gain in muscle mass and less body fat than consuming a similar amount of saturated fat. Since most of us are in positive energy balance, and consequently gain weight gradually over time, the present results are highly relevant for most western populations. Thus, although the results need confirmation, they are highly interesting from a public health point of view, with potentially important health implications for many populations. The long term consequences of accumulating more excess calories as liver and visceral fat as such are not clear, but may prove to markedly increase the risk of both cardiovascular disease and Type 2 diabetes in predisposed individuals.

Molecular and cardiometabolic responses

In the LIPOGAIN study we also discovered that overconsumption of saturated fats seems to activate certain genes in adipose tissue that may increase the storage of fat in the abdomen and at the same time hamper insulin regulation. Polyunsaturated fats, instead, could activate genes in visceral fat that in turn are linked to reduced storage of fat and improved sugar metabolism in the body. However, more research is required to understand how this occurs in humans.

Together with the marked differences in the fat storage in response to overeating saturated versus polyunsaturated fats, the LIPOGAIN study also demonstrated that overeating saturated fat increases the cardiovascular risk more than overeating polyunsaturated fat, mainly by increasing atherogenic lipoproteins. Thus, having sufficient amounts of polyunsaturated fats in the diet could not only prevent ectopic fat accumulation but also counteract some of the adverse cardiovascular effects caused by diet-induced weight gain.

Liver fat and visceral fat seem to contribute to a number of disturbances in metabolism. These findings can therefore be important for individuals prone to develop metabolic diseases such as diabetes. If the results regarding increased muscle mass following consumption of polyunsaturated fat can be confirmed in our future studies, it will potentially be interesting for many elderly people, for whom maintaining muscle mass is of great importance in preventing morbidity.

When it comes to the risk of developing diabetes and cardiovascular diseases, it seems more important where in the body the fat is stored than the total amount of stored body fat. Both excessive visceral fat and liver fat are closely associated with increased risk of developing Type 2 diabetes. These fat depots are therefore important targets for new drugs and dietary strategies. A number of studies have indicated that a higher intake of polyunsaturated fats from plant oils and nuts is associated with a decreased risk of Type 2 diabetes, but the reasons for this remain unclear. The findings from the LIPOGAIN study propose a potential explanation for such an association, showing that polyunsaturated fatty acids can affect body fat distribution more favourably than saturated fats, probably by regulating increased energy combustion or decreased storage of visceral fat in connection with calorie-rich diets.

Summary of the findings from the LIPOGAIN study:

  • Energy excess causes weight gain and obesity-related disease in the population;
  • Far from all obese individuals develop Type 2 diabetes or cardiovascular complications;
  • Among dietary components, fatty acids may play key roles in fat and glucose metabolism;
  • Fatty acids are signalling molecules and gene regulators and alter cell membranes;
  • Fatty acids, potentially together with such other nutrients as sugars, could alter ectopic fat storage and potentially also muscle mass gain in humans;
  • Dietary fat modification has the potential to prevent NAFLD, sarcopenic obesity and related metabolic diseases; and
  • Further research is needed in other populations and to identify mechanisms.

Implications and future perspectives

These discoveries may also explain why some individuals are more prone to accumulate fat in the liver and abdomen than others, and may suggest that the fat composition of the diet, in the long term, might play a role in preventing obesity-related disorders at an early stage before overweight develops. This is of great interest as we lack preventive treatments for fatty liver and visceral fat today. The new findings also support international dietary recommendations, including the newly published, evidence-based Nordic nutritional recommendations, which, among other things, recommend replacing some saturated fat from meat, butter and palm oil, for example, with polyunsaturated fats from plant oils and fatty fish. Here we need more research, and it is important to investigate this topic in a large pan-European study, both to investigate the long term impact of different dietary modifications on development of pre-diabetes and diabetes, and also to reveal the mechanisms behind this. We aim to find out in greater detail what happens in the body when we eat the respective fats and to study what the effects are in overweight individuals with elevated risk of Type 2 diabetes. We also aim to further examine the interaction between excess fats and sugars, i.e. fructose, on both ectopic fat and muscle mass and function.

Randomised studies are needed

To gain further knowledge, intervention studies are needed, not only to investigate nutritional effects in vivo, proof-of-efficacy and proof-of-concepts but also to identify mechanisms when combined with molecular and cellular studies in tissue and blood samples. Such data could be combined with other experiments. At the CNM, we have studied the effect of different foods, diets and nutrients for more than three decades using highly controlled dietary intervention studies. A number of research areas are investigated at CNM. We and other groups have gained much knowledge in the field, but findings from short term feeding trials need to be tested in large scale, controlled trials using appropriate methodology and study design, preferably combining novel high-tech methodology with state-of-the-art established techniques for assessing and evaluating food and dietary intake. Investigating the mechanisms by functional imaging (i.e. PET-MRI) and collecting tissue biopsies are useful approaches we will use in combination with systems biology techniques (e.g. global gene and protein profiling, and metabolomic profiling).

Research funding and support

The research at CNM is conducted at Uppsala University Hospital and Uppsala University in collaboration with other Swedish groups, and is among others supported by the Swedish Research Council and undertaken within the framework of EXODIAB – Excellence of Diabetes Research in Sweden.

References:

Rosqvist F et al. Diabetes. 2014;63:2356-68.

Iggman D et al. J Amer Heart Assoc. 2014;3(5).pii: e001095.doi:10.1161.

Risérus U, Willett W, Hu F. Prog Lip Res. 2009;48; 44-51.

 

Dr Ulf Risérus
Associate Professor
Clinical Nutrition and Metabolism Group
Department of Public Health and Caring Sciences
Uppsala University, Sweden
tel: +46 186117971

http://www.pubcare.uu.se/research/clinical_nutrition/?languageId=1