Central leptin insufficiency syndrome: An interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions

Abstract

This review critically reappraises recent scientific evidence concerning central leptin insufficiency versus leptin resistance formulations to explain metabolic and neural disorders resulting from subnormal or defective leptin signaling in various sites in the brain. Research at various fronts to unravel the complexities of the neurobiology of leptin is surveyed to provide a comprehensive account of the neural and metabolic effects of environmentally-imposed fluctuations in leptin availability at brain sites and the outcome of newer technology to restore leptin signaling in a sitespecific manner. The cumulative new knowledge favors a unified central leptin insufficiency syndrome over the, in vogue, central resistance hypothesis to explain the global adverse impact of deficient leptin signaling in the brain. Furthermore, the leptin insufficiency syndrome delineates a novel role of leptin in the hypothalamus in restraining rhythmic pancreatic insulin secretion while concomitantly enhancing glucose metabolism and non-shivering thermogenic energy expenditure, sequalae that would otherwise promote fat accrual to store excess energy resulting from consumption of energy-enriched diets. A concerted effort should now focus on development of newer technologies for delivery of leptin or leptin mimetics to specifically target neural pathways for remediation of diverse ailments encompassing the central leptin insufficiency syndrome.

Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

“…2,8,10,15,23,33,34 In this context, recent attention has been devoted to the disclosure that dynamic physiological fluctuations in circulating titers of leptin, a hormone produced primarily by white adipose tissue under the direction of insulin, have a critical role in conferring glucose homeostasis indirectly through the central nervous system. 10,16,[35][36][37][38][39][40][41][42] The goals of this review are to collate major contributions emanating from research conducted with the aid of gene transfer technology in unraveling the neural etiology of this chronic disease of hyperglycemia, which is correctable by leptin gene therapy confined selectively to the hypothalamus, and that this neurotherapy can be gainfully employed to forestall the pathogenesis of diabetes and varied attendant comorbidities.…”

“…10,33 How these two circuitries relay appropriate signals under the direction of circulating leptin for weight homeostasis has been reviewed extensively. 10,16,23,33,35,42,45,46 More recently, a third leptin-responsive circuit in the hypothalamus, the fat accrual network (FAN) that operates independent of appetite regulating network and EEN to augment glucose metabolism and disposal in the periphery on the one hand, and restrain pancreatic insulin secretion, on the other hand, has been identified ( Figure 1). 10 Whether this hypothalamic circuit may have a significant role in the pathogenesis of diabetes is reinforced by the following evidence:…”

“…This inference seemingly appeared discordant with the epidemiological surveys showing increased risks of diabetes type 2 paralleling hyperleptinemia and obesity. 1,8,9,14,17,18 However, a critical review 42 of leptin concentrations in cerebrospinal fluid consistently showed that hyperleptinemia either manifesting gradually in association with age-related obesity or that produced rapidly by consumption of energy-enriched diets, was associated with decreased brain leptin concentrations in rodents and humans (Figure 1). [62][63][64][65][66][67] This diminution in brain leptin levels was attributable to restricted leptin entry across the BBB due to downregulation of leptin transport receptors on central nervous system vasculature caused by the unrelenting action of raging hyperleptinemia associated with increasing adiposity.…”

“…5,7,69,70 Thus, insufficiency in leptin signaling in the hypothalamus caused by either decreased availability of leptin for transport to hypothalamus in the case of leptinopenia, or restricted leptin entry across BBB imposed by hyperleptinemia in obese subjects, is primarily responsible for impelling hyperglycemia and hyperinsulinemia, the antecedent pathophysiologic sequelae, persistence of which culminate in diabetes mellitus. 7,42 One is then confronted with the obvious questions of whether and how restoration of optimal leptin signaling in the hypothalamus would offer a new interventional therapeutic modality for this chronic disease.…”

“…26,36,37,53,59,75 These procedures were tedious, allowed only short-term delivery, required constant surveillance and were invariably associated with widespread distribution of leptin to targets within and outside the brain into the periphery where leptin was likely to increase the risks for multiple neural and peripheral ailments. 1,9,15,42,70,76,77 An injection of recombinant adenovirus-encoding leptin gene (Ad-lep) produced hyperleptinemia over several weeks suppressed weight gain, adiposity and blood insulin levels in normal adult rats. 78 These benefits were attributable to increased activation of hypothalamic leptin signaling because ablation of the basal hypothalamus abolished these hyperleptinemia-induced responses.…”