Reversal of Diet-Induced Obesity Increases Insulin Transport into Cerebrospinal Fluid and Restores Sensitivity to the Anorexic Action of Central Insulin in Male Rats

Abstract

Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.

Impaired insulin action in the human brain: causes and metabolic consequences

“…Indeed, animal research indicates that the effect of the action of insulin in the brain on regulation of body weight can be restored when rodents with dietinduced obesity lose weight. 153 Potentially, therefore, weight loss might also restore the favourable effects of the action of insulin in the brain in humans. However, human studies of the effects on brain insulin sensitivity of dietinduced weight loss or antidiabetic drugs such as glucagon like peptide 1 receptor agonists 154 or sodium-glucose cotransporter 2 inhibitors 155 (both of which promote weight loss) are lacking.…”

High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats

“…For the third cerebroventricular (I3VT) experiment, rats were outfitted with a cannula (Plastics One, Roanoke, VA) directed toward the I3VT, and correct placement was confirmed as previously described (8). Briefly, rats were anesthetized with intraperitoneal ketamine (70 mg/kg) and xylazine (6 mg/kg).…”

Interactions between the central nervous system and pancreatic islet secretions: a historical perspective

“…This indicates that obesity results in insulin resistance in the CNS as well as in peripheral tissues. The transport of insulin through the BBB is also compromised in diet-induced obesity (18,65), and it is possible that this effect is secondary to the leptin resistance that occurs with weight gain (73), given that there is some evidence indicating that the hypophagic effects of insulin require leptin functioning (64,156). When insulin and leptin are both administered centrally, most doses elicit additive leptin-insulin hypophagic effects.…”