Obese men respond to cognitive but not to catabolic brain insulin signaling

Abstract

Context and objective: Insulin acts in the brain to reduce food intake and body weight and is considered a major adiposity signal in energy homeostasis. In normal-weight men, intranasal insulin administration reduces body fat and improves declarative memory. The present experiments aimed to generalize these findings to obese patients, with a view to evaluate the therapeutic potential of the compound. Design, subjects and measurements: Insulin and placebo, respectively, were intranasally administered four times a day (amounting to 160 IU day À1 ) over 8 weeks to two groups of 15 obese men each. Results: Contrasting with the catabolic effects in normal-weight men, insulin treatment did not induce any significant reduction of body weight (P40.50) and body fat (P40.44) in the obese subjects. However, in accordance with the effects in normalweight men, declarative memory and mood were improved (Po0.05) and hypothalamic-pituitary-adrenal axis activity as assessed by circulating ACTH (Po0.01) and cortisol levels (Po0.04) was reduced. Conclusions: Our results indicate that in obese men, intranasal insulin is functionally active in the central nervous system but fails to affect the neuronal networks critically involved in body weight regulation. We conclude that obesity in men is associated with central nervous resistance to the adiposity signal insulin. This defect likely contributes to the persistence of obesity in spite of elevated levels of circulating insulin in obese patients.

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

“…Here, correlational analyses revealed that the effects of insulin on cortical activity were negatively related to the amount of body fat and the degree of peripheral insulin resistance. This outcome contrasts with the fact that, after 8 weeks of intranasal insulin treatment, obese participants displayed preserved susceptibility to the memory-improving effect of insulin [18] in as much as the storage of declarative memory representations also involves neocortical brain areas. However, during i.v.…”

“…Thus, intranasal administration of neuropeptides to target brain functions might be of particular therapeutic relevance because it bypasses the BBB. However, in pilot experiments in obese men, 8 weeks of intranasal insulin treatment had no effect on body weight and body fat mass [18]. Nevertheless, insulin administration improved declarative memory functions and reduced HPA axis secretory activity, effects that resemble those observed in normal-weight participants [20,25].…”

“…Thus intranasal insulin administration to increase central nervous availability of the hormone, although apparently ineffective in reducing body weight in the obese state [18], reduces HPA axis activity [18,20,25] and may thus counteract the development of visceral obesity, as well as cognitive impairments assumed to be promoted by excessive HPA axis secretion related to chronic stress. Likewise, boosting hypothalamic insulin signalling may help normalise dysregulated hepatic gluconeogenesis [7], a hallmark of type 2 diabetes and peripheral insulin resistance [34], which appears to be highly associated with central nervous insulin resistance [39].…”

“…infusion of the hormone is severely limited by the emergence of strong systemic side effects mainly on blood glucose concentrations and by the constraints of BBB transport [2]. Intranasal insulin administration bypasses uptake into the bloodstream and allows direct access to the cerebrospinal fluid (CSF) compartment within 30 min [15] without relevant changes in blood glucose and serum insulin levels [15][16][17][18][19][20]. Intranasally administered peptides may reach the brain along olfactory but also trigeminal pathways [21].…”

Novel Vasoconstrictor Formulation to Enhance Intranasal Targeting of Neuropeptide Therapeutics to the Central Nervous System

“…In addition to these neural pathways, perivascular pathways, and pathways involving the cerebrospinal fluid (CSF) or nasal lymphatics may play a central role in the distribution of therapeutics from the nasal cavity to the CNS (Thorne et al, 2004). Numerous therapeutics have been delivered to the CNS following intranasal administration and have demonstrated pharmacological effects in animals and in humans (Dhanda et al, 2005), with clinical investigations currently underway for intranasal treatment of Alzheimer's disease (Gozes and Divinski, 2007;Reger et al, 2008) and obesity (Hallschmid et al, 2008).…”