Hypothalamic Control of Energy Homeostasis

The hypothalamus has long been known to be involved in the control of energy homeostasis and metabolism by acting as a key integrator and transducer of central and peripheral hormonal and nutritional inputs [1] [2]. The 12 articles in this Special Issue review and discuss different aspects of the central regulation of whole-body energy metabolism, from the hypothalamic circuitries and molecular pathways involved in the regulation of food intake, energy expenditure, and glucose homeostasis, to the increasing number of peripheral metabolic signals that inform the central nervous system (CNS) on the body energy status, and the emerging role of novel actors mediating the hypothalamic response to metabolic challenges.

Dr. Tena-Sempere examines the impact of the metabolic state of the organism on reproductive maturation and function, using 2 key peripheral metabolic players, leptin and ghrelin, as model molecules [3]. He reviews the current knowledge on the direct and indirect effects of these hormones on the activity of central GnRH and Kiss1 neurons and their hypothalamic intracellular effectors, such as the mTORC1 pathway [3]. Another key intracellular sensor and transducer of the cell metabolic status, which has been recently shown to exert central metabolic actions, is Sirtuin 1 (SIRT1) [4]. The paper by Dr. Nogueiras’ group summarizes the main actions and molecular pathways triggered by brain Sirt1 to control feeding behavior, energy expenditure, glucose metabolism, and insulin sensitivity [5].

Special attention has been paid in this Special Issue to present data on novel peripheral or central mediators with emerging roles in the control of metabolism. Thus, Dr. Valet and collaborators discuss the biology of the apelin/APJ system, from the identification of apelin as a novel adipokine by this group in 2005 [6], to its central and peripheral actions, the characterization of APJ activated pathways, and its relevance as a promising target for treating metabolic disorders [7]. Similar interest as therapeutic potentials for metabolic diseases has been raised for the secretin family of brain-gut peptides and their receptors, which are presented in the thorough review by Drs. Sekar and Chow, who provide new avenues for research on hypothalamic secretin-related peptides [8]. Likewise, the role of nesfatin-1 and its precursor, NUCB2, which are produced both in adipocytes and in the brain [9], on food intake and body weight are discussed by Drs. Stengel and Taché [10]. These authors also describe the current evidence on the signaling pathways activated by nesfatin through its binding to an as yet unknown, putative Gi/o protein-coupled receptor. Centrally produced peptides, including the RFamide-related peptide family member, QRFP, are also reviewed in this Special Issue. In their paper on QRFP, Dr. Primeaux and co-workers provide a complete overview on the hypothalamic and extra-hypothalamic distribution, receptors, intracellular signaling pathways and mediators (i. e., leptin and hypothalamic NPY and POMC-producing neurons), and orexigenic effects, especially on fat intake, exhibited by this peptide [11]. The current data on the adipokine obestatin are discussed by Dr. Granata [12]. Although the activity of obestatin on the orphan receptor GPR39 and its role on food intake are a matter of controversy, the regulatory effects of this peptide on glucose and lipid metabolism together with its anti-inflammatory action make obestatin a promising candidate in the treatment of obesity and insulin resistance.

Two articles in this Special Issue debate the effects of neonatal nutrition on hypothalamic mechanisms controlling energy balance, introducing the concept of metabolic programming and its relevance in the development of obesity and associated metabolic diseases. Specifically, the paper by Dr. López and his group review the current state-of-knowledge on the impact of perinatal overfeeding on the hypothalamic circuits regulating food intake and body weight homeostasis, paying special attention to the peripheral signals that convey the nutritional information to the hypothalamus [13]. On the other hand, Dr. Wattez’s review is focused on the short-term and long-lasting alterations evoked by maternal or perinatal malnutrition on the hypothalamic melanocortin system [14].

One of the most exciting discoveries on the CNS mechanisms that regulate systemic metabolism is the recently demonstrated role of glial cells in central glucose sensing [15]. These novel findings are discussed by Drs. Tonon, Morin, and co-workers, who provide an updated overview of the functional interplay between glial cells and neurons, including their own data on the hypothalamic glial-derived endozepine, ODN [16]. We have included 2 reviews, written by Dr. Fernandez-Real’s and Dr. Dutour’s groups, which summarize the contribution of adipose tissue depots to the regulation of energy homeostasis under both physiological conditions and in response to increased fat mass [17] [18]. Understanding adipose tissue function, both as a source and as a target of metabolic signals, is essential to gain an integrative view on the metabolic control of energy homeostasis.

We wish to express our gratitude to the authors and the reviewers for their excellent and valuable contributions to this Issue, Mrs Catherine Beau, and the HMR staff for their continuous ­support.

We hope and trust that you will enjoy this Special Issue of ­Hormone and Metabolic Research – Hypothalamic Control of Energy Homeostasis.

• References

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• 2 Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 2006; 443: 289-295
• 3 Tena-Sempere M. Interaction between energy homeostasis and reproduction: central effects of leptin and ghrelin on the reproductive axis. Horm Metab Res 2013; 45: 919-927
• 4 Ramadori G, Lee CE, Bookout AL, Lee S, Williams KW, Anderson J, Elmquist JK, Coppari R. Brain SIRT1: anatomical distribution and regulation by energy availability. J Neurosci 2008; 28: 9989-9996
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