Carbohydrate regulation of lipid metabolism

Rationale: In long-term obesity, de novo lipogenesis (DNL) in adipose tissue is decreased, and lipids accumulate in ectopic sites such as liver and muscie. Altered lipid metabolism and storage is implicated in the development of insulin resistance and the metabolic syndrome. Intake of simple carbohydrates may be linked with altered DNL and ectopic fat accumulation.
Objective: To study the mechanisms underlying ectopic fat accumulation (in liver) by intake of fructose versus glucose in relation to insulin resistance in obese humans
Subjects and methods: In this observational study of obese adults that are scheduled for bariatric surgery (n=36), we will combine gold-standard isotope tracer studies to assess metabolic fluxes in vivo and analyses of human tissue biopsies. Obese subjects will be divided into groups with or without hepatic steatosis (i.e. liver fat content > or <5.56%) by magnetic resonance spectroscopy. Endogenous glucose production, hepatic insulin sensitivity, peripheral insulin sensitivity and adipose tissue lipolysis will be assessed during a two-step euglycemic hyperinsulinemic clamp with infusion of [6,6-2H2]glucose and [1,1,2,3,3-2H5]glycerol. On another visit, subjects will be randomly assigned (1:1) to consume a drink containing either fructose (75 grams in 225 ml water) or glucose (75 grams in 225 ml water), and lipid metabolism will be assessed in response to either fructose or glucose ingestion. Subjects will consume the same drink containing either fructose or glucose two hours before surgery, and biopsies from liver and abdominal fat compartments will be taken during bariatric surgery. Regulation of gene, protein and metabolite expression by intake of fructose or glucose will be assessed in insulin-sensitive tissues.
Main endpoints: Differences in the regulation of carbohydrate response/lipogenesis pathways, and the in vivo DNL flux by fructose versus glucose. Relationships between fat distribution/ectopic fat accumulation, in vivo lipid/carbohydrate fluxes, hepatic/peripheral insulin sensitivity, tissue lipid composition and gene/protein expression profiles.

We hypothesize that i) as compared to healthy obese humans, metabolically unhealthy obese humans, characterized by ectopic fat accumulation and insulin resistance, show an enhanced lipogenic response in liver and a lower lipogenic response in adipose tissue after a fructose as compared to glucose challenge, and ii) fructose as compared to glucose has a higher lipogenic potential in liver due to preferential metabolism by the liver.

- baseline (t = 0)

- study measurements (t = 1 to 3 weeks)

- bariatric surgery (t = 4 weeks)

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