Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults

Abstract

Resistance to the action of insulin affects fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver, and triglyceride export from the liver. To understand the metabolic consequences of hepatic fatty acid synthesis, partitioning, oxidation, and net liver fat content in the fasted and postprandial states, we used stable-isotope tracer methodologies to study healthy men and women with varying degrees of insulin resistance before and after consumption of a mixed meal. Subjects were classified as being normoinsulinemic (NI) (fasting plasma insulin <11.2 mU/L, n = 18) or hyperinsulinemic (HI) (fasting plasma insulin >11.2 mU/L, n = 19). Liver fat content was similar between HI and NI individuals, despite HI subjects having marginally more visceral fat. However, de novo lipogenesis was higher and fatty acid oxidation was lower in HI individuals compared with NI subjects. These data suggest that metabolic pathways promoting fat accumulation are enhanced in HI but, paradoxically, without any significant effect on liver fat content when observed in healthy people. This is likely to be explained by increased triglyceride secretion as observed by hypertriglyceridemia.

Hepatic fatty acid synthesis and partitioning: the effect of metabolic and nutritional state

“…No direct assessment of hepatic CO 2 production has been undertaken in human subjects over the postprandial period; however plasma concentrations of 3-OHB have been measured. We have previously found mixed results with some of our studies showing a significantly lower (27) , similar (38) or higher (22) postprandial response of blood 3-OHB in insulin-resistant compared with insulin-sensitive individuals. We have also found that men have a notably lower postprandial 3-OHB concentration when compared with women (10) .…”

“…This will complement the suppression of fatty acid release from adipose tissue which is under the influence of insulin. Indeed, we have previously found strong inverse associations between hepatic DNL and plasma 3-OHB concentrations in the postprandial period in some, but not all, of our participants (10,38) suggesting a dissociation between the pathways. It could be speculated that some individuals have hepatic insulin resistance (which is not obvious at a systemic level) and this leads to a lack of suppression in ketone body production in the postprandial period.…”

“…The synthesis of one molecule of palmitoyl-CoA from acetyl-CoA is an energy inefficient process costing seven molecules of ATP and requiring the conversion of fourteen highenergy NADPH molecules to NADP+ (33) . Despite being energetically inefficient and likely a minor route for storing excess energy, the contribution of de novo fatty acids to VLDL-TAG has been reported to be up to about 10 % in healthy, insulin-sensitive adults (10,19,(34)(35)(36)(37)(38) and 14-22 % in individuals with insulin resistance or NAFLD (8,34,(36)(37)(38) . As individuals with insulin resistance/NAFLD have notably higher hepatic DNL compared with those without, it is often speculated, although unsubstantiated, that enhanced DNL is a causal factor in the development of insulin resistance/ NAFLD; thus it remains unclear if insulin resistance/ NAFLD causes enhanced hepatic DNL or vice versa.…”

Hepatic de novo lipogenesis is suppressed and fat oxidation is increased by omega-3 fatty acids at the expense of glucose metabolism

“…The evening prior to the study day, subjects consumed deuterated water ( 2 H 2 O) (3 g/kg body water) and continued to consume 2 H 2 O during the course of the study day for the measurement of fasting and postprandial hepatic DNL. 24 On the study day, after an overnight fast and consumption of 2 H 2 O, subjects came to the Clinical Research Unit and a cannula was inserted into an antecubital vein and baseline (Time 0) blood and breathe samples taken. Participants were then fed a mixed test meal, consisting of 40 g Rice Krispies (Kelloggs, Manchester, UK), 200 g skimmed milk and a chocolate drink containing 40 g olive oil (40 g fat, 40 g carbohydrate).…”

Gut‐derived short‐chain fatty acids: A friend or foe for hepatic lipid metabolism?

“…Increased hepatic DNL is also reported in hyperinsulinemic individuals, compared with those with normal glucose homeostasis (Pramfalk et al . ). Based on our observations, we propose that the acetate derived from inulin fermentation would have contrasting effects on hepatic lipid content depending on the metabolic health of the individual.…”