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The Neuroanatomical Axis for Control of Energy Balance

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Abstract

The hypothalamic feeding-center model, articulated in the 1950s, held that the hypothalamus contains the interoceptors sensitive to blood-borne correlates of available or stored fuels as well as the integrative substrates that process metabolic and visceral afferent signals and issue commands to brainstem mechanisms for the production of ingestive behavior. A number of findings reviewed here, however, indicate that sensory and integrative functions are distributed across a central control axis that includes critical substrates in the basal forebrain as well as in the caudal brainstem. First, the interoceptors relevant to energy balance are distributed more widely than had been previously thought, with a prominent brainstem complement of leptin and insulin receptors, glucose-sensing mechanisms, and neuropeptide mediators. The physiological relevance of this multiple representation is suggested by the demonstration that similar behavioral effects can be obtained independently by stimulation of respective forebrain and brainstem subpopulations of the same receptor types (e.g., leptin, CRH, and melanocortin). The classical hypothalamic model is also challenged by the integrative achievements of the chronically maintained, supracollicular decerebrate rat. Decerebrate and neurologically intact rats show similar discriminative responses to taste stimuli and are similarly sensitive to intake-inhibitory feedback from the gut. Thus, the caudal brainstem, in neural isolation from forebrain influence, is sufficient to mediate ingestive responses to a range of visceral afferent signals. The decerebrate rat, however, does not show a hyperphagic response to food deprivation, suggesting that interactions between forebrain and brainstem are necessary for the behavioral response to systemic/metabolic correlates of deprivation in the neurologically intact rat. At the same time, however, there is evidence suggesting that hypothalamic–neuroendocrine responses to fasting depend on pathways ascending from brainstem. Results reviewed are consistent with a distributionist (as opposed to hierarchical) model for the control of energy balance that emphasizes: (i) control mechanisms endemic to hypothalamus and brainstem that drive their unique effector systems on the basis of local interoceptive, and in the brainstem case, visceral, afferent inputs and (ii) a set of uni- and bidirectional interactions that coordinate adaptive neuroendocrine, autonomic, and behavioral responses to changes in metabolic status.

References (211)

  • MA Cowley et al.

    Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: Evidence of a cellular basis for the adipostat

    Neuron

    (1999)
  • M Dallaporta et al.

    Involvement of adenosine triphosphate-sensitive K+ channels in glucose-sensing in the rat solitary tract nucleus

    Neurosci Lett

    (2000)
  • S Diano et al.

    Segregation of the intra- and extrahypothalamic neuropeptide Y and catecholaminergic inputs on paraventricular neurons, including those producing thyrotropin-releasing hormone

    Regul Pept

    (1998)
  • CF Elias et al.

    Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area

    Neuron

    (1999)
  • JK Elmquist et al.

    From lesions to leptin: Hypothalamic control of food intake and body weight

    Neuron

    (1999)
  • RA Fay et al.

    Identification of rat brainstem multisynaptic connections to the oral motor nuclei using pseudorabies virus. I. Masticatory muscle motor systems

    Brain Res Brain Res Rev

    (1997)
  • FW Flynn et al.

    Fourth ventricular phlorizin dissociates feeding from sympathoadrenal hyperglycemia in rats

    Brain Res

    (1985)
  • MI Friedman et al.

    Metabolic and physiologic effects of a hunger-inducing injection of insulin

    Physiol Behav

    (1982)
  • M Funahashi et al.

    Glucose-responsive neurons exist within the area postrema of the rat: In vitro study on the isolated slice preparation

    Brain Res Bull

    (1993)
  • SQ Giraudo et al.

    Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands

    Brain Res

    (1998)
  • AP Goldstone et al.

    Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents

    FEBS Lett

    (1997)
  • HJ Grill et al.

    Long-term effects on feeding and body weight after stimulation of forebrain or hindbrain CRH receptors with urocortin

    Brain Res

    (2000)
  • HJ Grill et al.

    The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats

    Brain Res

    (1978)
  • HJ Grill et al.

    The taste reactivity test. II. Mimetic responses to gustatory stimuli in chronic thalamic and chronic decerebrate rats

    Brain Res

    (1978)
  • SC Heinrichs et al.

    Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y

    Brain Res

    (1993)
  • JP Herman et al.

    Neurocircuitry of stress: Central control of the hypothalamo–pituitary–adrenocortical axis

    Trends Neurosci

    (1997)
  • S Higgs et al.

    Hyperphagia induced by direct administration of midazolam into the parabrachial nucleus of the rat

    Eur J Pharmacol

    (1996)
  • CC Horn et al.

    Brain fos-like immunoreactivity in chronic decerebrate and neurologically intact rats given 2,5-anhydro-d-mannitol

    Brain Res

    (1998)
  • D Huszar et al.

    Targeted disruption of the melanocortin-4 receptor results in obesity in mice

    Cell

    (1997)
  • SA Joseph et al.

    Efferent ACTH-IR opiocortin projections from nucleus tractus solitarius: A hypothalamic deafferentation study

    Peptides

    (1988)
  • JM Kaplan et al.

    Swallowing during ongoing fluid ingestion in the rat

    Brain Res

    (1989)
  • JM Kaplan et al.

    Food deprivation does not potentiate glucose taste reactivity responses of chronic decerebrate rats

    Brain Res

    (2000)
  • RS Ahima et al.

    Leptin

    Annu Rev Physiol

    (2000)
  • RS Ahima et al.

    Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia [See comments]

    Endocrinology

    (1999)
  • RS Ahima et al.

    Role of leptin in the neuroendocrine response to fasting

    Nature

    (1996)
  • DG Baskin et al.

    Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mRNA in the arcuate nucleus

    J Histochem Cytochem

    (1999)
  • LL Bernardis et al.

    The dorsomedial hypothalamic nucleus revisited: 1998 update

    Proc Soc Exp Biol Med

    (1998)
  • HR Berthoud et al.

    Ingestive behavior after intracerebral and intracerebroventricular infusions of glucose and 2-deoxy-d-glucose

    Am J Physiol

    (1977)
  • CJ Billington et al.

    Neuropeptide Y in hypothalamic paraventricular nucleus: A center coordinating energy metabolism

    Am J Physiol

    (1994)
  • J Bittencourt et al.

    Do centrally administered neuropeptides access cognate receptors?: An analysis in the central corticotropin-releasing factor system

    J Neurosci

    (2000)
  • JC Bittencourt et al.

    Urocortin expression in rat brain: Evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors

    J Comp Neurol

    (1999)
  • WW Blessing

    The Lower Brainstem and Bodily Homeostasis

    (1997)
  • DA Booth

    Food intake and chemical senses

  • MA Borg et al.

    Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats

    J Clin Invest

    (1997)
  • WP Borg et al.

    Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia

    J Clin Invest

    (1994)
  • WP Borg et al.

    Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release

    Diabetes

    (1995)
  • LS Brady et al.

    Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats

    Neuroendocrinology

    (1990)
  • JF Breininger et al.

    Fluorescence in situ hybridization of scarce leptin receptor mRNA using the enzyme-labeled fluorescent substrate method and tyramide signal amplification

    J Histochem Cytochem

    (2000)
  • C. Broberger

    Cocaine- and amphetamine-related transcript (CART) and food intake: Behavior in search of anatomy

    Drug Dev Res

    (2000)
  • C Broberger et al.

    Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to the neuropeptide Y and agouti gene-related protein systems

    J Comp Neurol

    (1998)
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