Leptin Increases: Physiological Roles in the Control of Sympathetic Nerve Activity, Energy Balance, and the Hypothalamic-Pituitary-Thyroid Axis

Abstract

It is well established that decreases in plasma leptin levels, as with fasting, signal starvation and elicit appropriate physiological responses, such as increasing the drive to eat and decreasing energy expenditure. These responses are mediated largely by suppression of the actions of leptin in the hypothalamus, most notably on arcuate nucleus (ArcN) orexigenic neuropeptide Y neurons and anorexic pro-opiomelanocortin neurons. However, the question addressed in this review is whether the effects of increased leptin levels are also significant on the long-term control of energy balance, despite conventional wisdom to the contrary. We focus on leptin's actions (in both lean and obese individuals) to decrease food intake, increase sympathetic nerve activity, and support the hypothalamic-pituitary-thyroid axis, with particular attention to sex differences. We also elaborate on obesity-induced inflammation and its role in the altered actions of leptin during obesity.

Keywords: arcuate nucleus; brown adipose tissue; diet-induced thermogenesis; energy expenditure; obesity; obesity-induced inflammation; paraventricular nucleus; selective leptin resistance; sex differences; weight regain.

Figure 1

Hypothalamic neurocircuitry by which leptin increases SNA and activates the HPT axis. NPY: Neuropeptide Y; POMC: Pro-opiomelanocortin; ArcN: Arcuate nucleus; PVN: Paraventricular nucleus; TRH: Thyrotropin-releasing hormone; TSH: Thyroid-stimulating hormone; TH: Thyroid hormone; OT: Oxytocin; EE: Energy expenditure; BAT SNA: Brown adipose tissue sympathetic nerve activity; RVLM: Rostral ventrolateral medulla; RPa: Raphe pallidus; DMH: Dorsomedial hypothalamus. Green arrows: stimulatory; red arrows: inhibitory. See text for description and details.

Figure 2

Hypothesized mechanisms underlying sex differences in the actions of elevated leptin and insulin levels to increase SNA during obesity. NPY: Neuropeptide Y; POMC: Pro-opiomelanocortin; ArcN: Arcuate nucleus; AngII: Angiotensin II; Ang-(1–7): Angiotensin 1–7; TyH: Tyrosine hydroxylase (marker of dopaminergic neurons); GABA: Gamma-aminobutyric acid; E2: Estrogen; SNA: Sympathetic nerve activity. Green arrows: stimulatory; red arrows: inhibitory. Dotted arrows indicate that NPY and POMC presympathetic neurons are resistant to the actions of leptin or insulin in obese females, whereas these actions are enhanced in obese males. See text and legend to Table 2 for details. Adapted in part from [24].