To ingest or rest? Specialized roles of lateral hypothalamic area neurons in coordinating energy balance

Abstract

Survival depends on an organism's ability to sense nutrient status and accordingly regulate intake and energy expenditure behaviors. Uncoupling of energy sensing and behavior, however, underlies energy balance disorders such as anorexia or obesity. The hypothalamus regulates energy balance, and in particular the lateral hypothalamic area (LHA) is poised to coordinate peripheral cues of energy status and behaviors that impact weight, such as drinking, locomotor behavior, arousal/sleep and autonomic output. There are several populations of LHA neurons that are defined by their neuropeptide content and contribute to energy balance. LHA neurons that express the neuropeptides melanin-concentrating hormone (MCH) or orexins/hypocretins (OX) are best characterized and these neurons play important roles in regulating ingestion, arousal, locomotor behavior and autonomic function via distinct neuronal circuits. Recently, another population of LHA neurons containing the neuropeptide Neurotensin (Nts) has been implicated in coordinating anorectic stimuli and behavior to regulate hydration and energy balance. Understanding the specific roles of MCH, OX and Nts neurons in harmonizing energy sensing and behavior thus has the potential to inform pharmacological strategies to modify behaviors and treat energy balance disorders.

Keywords: dopamine; feeding; lateral hypothalamic area; melanin concentrating hormone; neurotensin; obesity; orexin.

Figure 1

Projections Via Which the LHA Coordinates Behaviors that Impact Energy Balance. The LHA projects densely into brain regions that modulate motivated behaviors, such as feeding, drinking, physical activity and addiction to drugs of abuse. The LHA engages the motivational circuit via direct projections into the forebrain (NA) and to the midbrain (VTA), which in turn projects to reward areas of the brain such as the NA, mPFC and Hipp. The LHA also sends dense projections to hindbrain sites that regulate arousal/sleep and movement/vigilance, such as the LC and other sites not shown for sake of clarity. LHA projections onto neurons within the medulla in turn project via the spinal cord to engage the autonomic nervous system, thereby modulating heart rate, respiration, brown adipose tissue/thermogenesis and white adipose tissue to modulate energy storage. Specific neuronal subsets of the LHA engage some or all of these sites to coordinate energy cues and behavioral output that impacts energy balance, as reviewed in the text. Note that not all projections from the LHA are represented on this schematic, such as projections to the prefrontal cortex and hippocampus; though these likely have important roles in regulating physiology, they are beyond the scope of this review and thus have not been represented here. Abbreviations: LHA = lateral hypothalamic area, NA = nucleus accumbens, VTA = ventral tegmental area, mPFC = medial prefrontal cortex, Hipp = hippocampus, LC = locus coeruleus, Med = medulla, BAT = brown adipose tissue, WAT = white adipose tissue. Sagital brain outline adapted from Paxinos and Franklin (2001).