Differential effects of hypothalamic long-chain fatty acid infusions on suppression of hepatic glucose production

Abstract

Our objective was to investigate whether the direct bilateral infusion of the monounsaturated fatty acid (MUFA) oleic acid (OA) within the mediobasal hypothalamus (MBH) is sufficient to reproduce the effect of administration of OA (30 nmol) in the third cerebral ventricle, which inhibits glucose production (GP) in rats. We used the pancreatic basal insulin clamp technique (plasma insulin ∼20 mU/ml) in combination with tracer dilution methodology to compare the effect of MBH OA on GP to that of a saturated fatty acid (SFA), palmitic acid (PA), and a polyunsaturated fatty acid (PUFA), linoleic acid (LA). The MBH infusion of 200 but not 40 pmol of OA was sufficient to markedly inhibit GP (by 61% from 12.6 ± 0.6 to 5.1 ± 1.6 mg·kg(-1)·min(-1)) such that exogenous glucose had to be infused at the rate of 6.0 ± 1.2 mg·kg(-1)·min(-1) to prevent hypoglycemia. MBH infusion of PA also caused a significant decrease in GP, but only at a total dose of 4 nmol (GP 5.8 ± 1.6 mg·kg(-1)·min(-1)). Finally, MBH LA at a total dose of 0.2 and 4 nmol failed to modify GP compared with rats receiving MBH vehicle. Increased availability of OA within the MBH is sufficient to markedly inhibit GP. LA does not share the effect of OA, whereas PA can reproduce the potent effect of OA on GP, but only at a higher dose. It remains to be determined whether SFAs need to be converted to MUFAs to exert this effect or whether they activate a separate signaling pathway to inhibit GP.

Fig. 1.

Mediobasal hypothalamus (MBH) oleic acid enhances insulin action and inhibits glucose production. A: schematic representation of experimental procedure. Surgical implantation of bilateral cannulae was performed on day 1 (∼3 wk before the clamp study). Full recovery of body weight and food intake was seen by day 7. On day 14, iv catheters were placed. Pancreatic insulin clamp studies were performed on day 21. Infusions lasted a total of 360 min. MBH infusions were started at t = 0 min and maintained throughout the study. At t = 120 min, an infusion of labeled glucose was started and maintained throughout the next 4 h of the study. At t = 240 min, the infusions of insulin and somatostatin to maintain a basal clamp, along with a varying dose of glucose as needed to maintain euglycemia, were begun and continued for the next 2 h until the end of the study. B: dose-response curve showing concentration of long-chain fatty acyl-CoA (LCFA-CoA) per gram of protein in a small half-wedge of mediobasal hypothalamic tissue in response to local infusions of the various doses of oleic acid. C: effect of different doses of oleic acid on glucose infusion rate. D: effect of intrahypothalamic (IH) oleic acid on %decrease of glucose production during the clamp. E: effect of IH oleic acid on the rate of glucose production during the clamp. F: effect of oleic acid on the rate of glucose uptake. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 2.

Response of plasma glucose to IH fatty acids. Each bar is an average of at least 7 measurements between 2 and 4 h after the start of the IH infusion; n = 5 animals. A: oleic acid. Both the high and the medium doses of oleic acid caused a decrease in circulating glucose levels compared with IH vehicle and low-dose oleic acid. B: palmitic acid. Both the high and low dose of palmitic acid caused a trend toward decreased circulating glucose levels. C: linoleic acid. Neither low nor high doses of linoleic acid significantly decreased the circulating plasma glucose following 2 h of infusion. *P < 0.05, ***P < 0.001.

Fig. 3.

MBH palmitic acid, but not linoleic acid, enhances insulin action and inhibits glucose production, albeit not as potently as oleic acid. A: effect of high- and low-dose palmitic and linoleic acids on glucose infusion rate compared with the same doses of oleic acid. B: effect of MBH palmitic and linoleic acids on the rate of glucose production during the clamp. The rates of glucose production were similar in all groups before the start of the pancreatic insulin clamp studies. C: effect of IH palmitic and linoleic acids on %decrease of glucose production during the clamp. D: effect of palmitic and linoleic acids on the rate of glucose uptake. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 4.

MBH oleic and palmitic acids decrease hepatic glucose fluxes, but linoleic acid does not. Data shown are from animals treated with the medium dose, 200 pmol, of each fatty acid. A: gluconeogenesis. B: glycogenolysis. C: glucose cycling. D: total glucose output. *P < 0.05.