Review

. 2018 Sep;19(9):1205-1235.

doi: 10.1111/obr.12699. Epub 2018 May 14.

Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories

K L Stanhope¹, M I Goran², A Bosy-Westphal³, J C King⁴, L A Schmidt^{5

6

7}, J-M Schwarz^{8

9}, E Stice¹⁰, A C Sylvetsky¹¹, P J Turnbaugh¹², G A Bray¹³, C D Gardner¹⁴, P J Havel^{1

15}, V Malik¹⁶, A E Mason¹⁷, E Ravussin¹³, M Rosenbaum¹⁸, J A Welsh¹⁹, C Allister-Price¹, D M Sigala¹, M R C Greenwood¹⁵, A Astrup²⁰, R M Krauss⁴

Affiliations

¹ Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
² Department of Preventive Medicine, Diabetes and Obesity Research Institute, University of Southern California, Los Angeles, CA, USA.
³ Institute of Human Nutrition and Food Science, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
⁴ Children's Hospital Oakland Research Institute, Oakland, CA, USA.
⁵ Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, San Francisco, CA, USA.
⁶ California Clinical and Translational Science Institute, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Anthropology, History, and Social Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁸ Touro University, Vallejo, CA, USA.
⁹ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Oregon Research Institute, Eugene, OR, USA.
¹¹ Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA.
¹² Department of Microbiology and Immunology, G.W. Hooper Research Foundation, University of California, San Francisco, San Francisco, CA, USA.
¹³ Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
¹⁴ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Department of Nutrition, University of California, Davis, Davis, CA, USA.
¹⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁷ Department of Psychiatry, Osher Center for Integrative Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY, USA.
¹⁹ Department of Pediatrics, Emory University School of Medicine, Wellness Department, Children's Healthcare of Atlanta, Nutrition and Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, GA, USA.
²⁰ Department of Nutrition, Exercise, and Sports, Faculty of Sciences, University of Copenhagen, Copenhagen, Denmark.

PMID: 29761610
PMCID: PMC6530989
DOI: 10.1111/obr.12699

Review

Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories

K L Stanhope et al. Obes Rev. 2018 Sep.

. 2018 Sep;19(9):1205-1235.

doi: 10.1111/obr.12699. Epub 2018 May 14.

Authors

Affiliations

¹ Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
² Department of Preventive Medicine, Diabetes and Obesity Research Institute, University of Southern California, Los Angeles, CA, USA.
³ Institute of Human Nutrition and Food Science, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
⁴ Children's Hospital Oakland Research Institute, Oakland, CA, USA.
⁵ Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, San Francisco, CA, USA.
⁶ California Clinical and Translational Science Institute, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Anthropology, History, and Social Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁸ Touro University, Vallejo, CA, USA.
⁹ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Oregon Research Institute, Eugene, OR, USA.
¹¹ Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA.
¹² Department of Microbiology and Immunology, G.W. Hooper Research Foundation, University of California, San Francisco, San Francisco, CA, USA.
¹³ Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
¹⁴ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Department of Nutrition, University of California, Davis, Davis, CA, USA.
¹⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁷ Department of Psychiatry, Osher Center for Integrative Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY, USA.
¹⁹ Department of Pediatrics, Emory University School of Medicine, Wellness Department, Children's Healthcare of Atlanta, Nutrition and Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, GA, USA.
²⁰ Department of Nutrition, Exercise, and Sports, Faculty of Sciences, University of Copenhagen, Copenhagen, Denmark.

PMID: 29761610
PMCID: PMC6530989
DOI: 10.1111/obr.12699

Abstract

Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference 'Diet and Cardiometabolic Health - Beyond Calories', and this paper summarizes the presentations and follow-up discussions. Regarding the health effects of dietary fat, sugar and non-nutritive sweeteners, it is concluded that food-specific saturated fatty acids and sugar-sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential 'beyond calories' mechanisms may lead to new strategies for attenuating the obesity crisis.

Keywords: Cardiometabolic disease; dietary fat; dietary sugar; obesity.

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Conflict of interest statement

The following authors have no conflicts of interest to report: Drs Schmidt, Turnbaugh and Bray.

The following authors acknowledge these conflicts of interest.

Dr Stanhope received honoraria from the CrossFit Foundation for serving as a Conference Academic Organizer and for writing the manuscript.

Dr Goran received honorarium from the CrossFit Foundation for serving on the Advisory Committee and travel reimbursement from the CrossFit Foundation for attending the conference in July 2017.

Drs Bosy-Westphal, King, Schwarz, Sylvetsky, Gardner, Mason, Rosenbaum and Allister-Price and Ms Sigala received travel reimbursement from the CrossFit Foundation for attending the conference in July 2017.

Dr Malik received travel reimbursement from the CrossFit Foundation for attending the conference in July 2017. She was paid for consulting services by the City of San Francisco for litigation related to health warning labels of soda and is on a pro bono retainer to The Center for Science in the Public Interest for expert support in litigation related to sugar-sweetened beverages.

Dr Havel received travel reimbursement from the CrossFit Foundation for attending the conference in July 2017. He has received research grants from Bristol Myers Squibb and Arrowhead Pharmaceuticals.

Dr Stice received travel reimbursement from the CrossFit Foundation for attending the conference in July 2017. His institution has received research funding from Crave Crush, and he has received reimbursement for travel from Crave Crush.

Dr Ravussin received travel reimbursement from the CrossFit Foundation for attending the conference in July 2017. He serves on the Scientific Advisory Board to the Nutrilite Health Institute with Amway and for the Institute of Cardiometabolism and Nutrition in Paris, France; has a consultant contract with Janssen and with Nutrilite Health Institute with Amway; gives lectures at the Open Academy in Venice; and is a lecturer/advisor for the Center for Medical Weight Loss. He has received research grants or unrestricted gifts from Amway, Nestle, the Nutrition Science Initiative, Novartis, Sanofi-Aventis, Weight Watchers and Ethicon Surgery. He has a patent for ‘Night Moderate Hypoxia to Treat Insulin Resistance and Cardiometabolic Syndrome’.

Dr Welsh received travel reimbursement from the CrossFit Foundation for attending the conference in July 2017. She received payment from the Sugar Foundation for an analysis and presentation on sugar consumption in toddlers.

Dr Greenwood received honorarium for serving as Chairperson of the manuscript planning meeting and travel reimbursement from the CrossFit Foundation for attending the conference in July 2017.

Dr Astrup received honorarium from CrossFit Foundation for serving on the Advisory Committee and travel reimbursement from CrossFit Foundation for attending the conference in July 2017. He reports personal fees from Dutch Beer Institute, NL; Feast Kitchen A/S, Denmark; Groupe Éthique et Santé, France; McCain Foods Limited, USA; Nestlé Research Center, Switzerland; Weight Watchers, USA; BioCare Copenhagen, Zaluvida, Switzerland; Basic Research, USA; Beachbody, USA; Danish Agriculture & Food Council, Novo Nordisk, Denmark; Pfizer, Germany; Saniona, Denmark; Sanofi-Aventis, Germany; S-Biotek, Denmark; Scandinavian Airlines System, Denmark; and Tetra Pak, Sweden; personal fees and other from Gelesis, USA; grants from Arla Foods, DK; Danish Dairy Research Council; and Gelesis, USA outside the submitted work. In addition, Dr Astrup has a patents pending to the University of Copenhagen ‘Methods of inducing weight loss, treating obesity and preventing weight gain’ (licensee Gelesis, USA) and ‘Biomarkers for predicting degree of weight loss’ (licensee Nestec SA, CH), and he is a co-inventor of a number of other patents owned by the University in accordance with Danish law. Astrup receives royalties for the books Verdens Bedste Kur, Politikens Forlag, Denmark, 2012 (subsequently published in English as World’s Best Diet, Penguin, Australia, and The Nordic Way, Random House, USA), and Spis dig slank efter dit blodsukker (Eat according to your blood sugar and be slim), Politikens Forlag, Denmark, 2017. He is a co-author of several books in the pipeline about personalized nutrition for weight loss; a co-owner and member of the board of the consultancy company Dentacom Aps, Denmark, co-founder; and a co-owner of UCPH spin-outs Mobile Fitness A/S & Flaxslim ApS (where he is also a member of the board, 2015–present) and Personalized Weight Management Research Consortium ApS (Gluco-diet.dk/2017–present).

Dr Krauss received honorarium from CrossFit Foundation for serving on the Advisory Committee and travel reimbursement from CrossFit Foundation for attending the conference in July 2017. He has received payment for services on the Scientific Advisory Board of Virta Health and from Quest Diagnostics for services on speakers bureau. He has received research grants from the Almond Board of California and The Dairy Research Institute. He has a patent on lipoprotein particle analysis.

Figures

**Figure 1**
The potential links between dietary patterns and components and cardiometabolic risk. The totality of the evidence suggests that added sugar and certain saturated-fat-containing foods increase risk for cardiometabolic disease by metabolic mechanisms that are not mediated solely by positive energy balance and fat gain. There is also evidence that certain dietary patterns or components can increase ‘energy in’ and/or ‘energy storage as fat’ via mechanisms that are not explained solely by their specific contribution of calories to the ‘energy in’ side of the energy balance equation. The strength of the links is indicated by the green lines as follows. *Solid green line*: supported by evidence from animal studies and clinical observational and dietary intervention studies. *Dashed line*: evidence from prospective cohort studies and/or clinical dietary intervention studies suggests heightened risk during critical developmental periods and in persons with compromised glucose tolerance or insulin sensitivity. *Dotted line*: supported mainly by evidence from observational and/or animal studies only. *Dotted line w/X*: evidence from 100% of the clinical dietary intervention studies do not support the evidence from the observational and animal studies.

**Figure 2**
Established paradigm by which positive energy balance promotes the development of the metabolic syndrome. Positive energy balance leads to fat accumulation and larger and more insulin-resistant adipocytes (a). The insulin resistance increases lipolytic activity and circulating free fatty acids (FFA) (b). While lipolytic activity is higher in visceral adipose tissue than subcutaneous adipose, upper body subcutaneous adipose is a major contributor to the increased levels of FFA (328,329). High levels of FFA can mediate muscle (c) (330) and liver (d) (331) insulin resistance. Hepatic uptake of FFA leads to increased liver lipid (e), which is associated with liver insulin resistance (f) (332) and promotes very-low-density lipoprotein (VLDL) production/secretion (g) and dyslipidaemia (h) (328,333). Increased exposure to circulating triglyceride promotes intramyocellular lipid accumulation (i) (334), which is associated with insulin resistance (j) and type 2 diabetes (332). Inflammatory factors released by insulin-resistant visceral adipose tissue (k) may also promote hepatic insulin resistance (l) and lipid accumulation (m) (119).

**Figure 3**
Potential mechanisms by which consumption of fructose promotes the development of metabolic syndrome The initial phosphorylation of dietary fructose in the liver is largely catalysed by fructokinase C (a), which is not regulated by hepatic energy status (122,123). This results in unregulated fructose uptake and metabolism by the liver. The excess substrate leads to increased *de novo* lipogenesis (DNL) (b) (117,127). DNL increases the intra-hepatic lipid supply directly (–129), via synthesis of fatty acids (c), and indirectly by inhibiting fatty acid oxidation (d) (120,127). Increased intra-hepatic lipid content promotes very-low-density lipoprotein (VLDL) production and secretion (e) (130). This leads to increased levels of circulating triglyceride (TG) and low-density lipoprotein particles (dyslipidaemia) (f) (131), risk factors for cardiovascular disease (CVD) (g). Increased levels of hepatic lipid may also promote hepatic insulin resistance (132) by increasing levels of diacylglycerol, which may activate novel protein kinase C and lead to serine phosphorylation (serine P) of the insulin receptor and insulin receptor substrate 1 and impaired insulin action (h) (335). Because of selective insulin resistance, DNL is even more strongly activated in the insulin resistant liver (i) (336), which has the potential to generate a vicious cycle (circular arrows) that would be perpetuated by sustained fructose consumption. This cycle would be expected to further exacerbate VLDL production and secretion via increased intrahepatic lipid supply (130). Hepatic insulin resistance also promotes VLDL production/secretion (j) by increasing apolipoprotein B availability (337,338) and apolipoprotein CIII synthesis (339) and by up-regulating microsomal TG transfer protein expression (MTP) (336). This exacerbates and sustains exposure to circulating TG, leading to intramyocellular lipid accumulation (k) (334), impaired insulin signalling and whole-body insulin resistance (l) (332). The fructokinase-catalysed phosphorylation of fructose to fructose-1-phosphate, which results in conversion of adenosine triphosphate to adenosine monophosphate and a depletion of inorganic phosphate, leads to uric acid production via the purine degradation pathway (m) (,–125). High levels of uric acid are associated and may contribute to increased risk for development of fatty liver (n) and CVD (o) (–342). Fructose exposure in the intestine (p) (134,135) and liver (q) (136) and fructose-induced increases of visceral adipose (r) may promote inflammatory responses (117,343) that further promote liver lipid accumulation (s) and/or impair hepatic insulin signalling (t) (119).

**Figure 4**
(A) Reanalysed results from the NUGENOB Study: subjects with obesity, prediabetes and low fasting insulin lost more weight on a high-fat vs. low-fat diet. (B) Reanalysed results from the DioGenes Study: subjects with obesity, prediabetes and low fasting insulin regained three to four times less weight on a low–carbohydrate (CHO)/low-glycaemic-index (GI) diet than subjects with normal glycaemia and obesity. **P <* 0.05 from zero; ^#*P <* 0.05 between glycaemic/insulinaemic groups. Fasting plasma insulin (FPI). Modified from Hjorth *et al*. (226).

See this image and copyright information in PMC

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Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories

Affiliations

Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical