Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status

Abstract

Energy homeostasis is regulated in coordinate fashion by the brain-gut axis, the homeostatic energy balance circuitry in the hypothalamus and the hedonic energy balance circuitry comprising the mesolimbcortical A10 dopamine pathway. Collectively, these systems convey and integrate information regarding nutrient status and the rewarding properties of ingested food, and formulate it into a behavioral response that attempts to balance fluctuations in consumption and food-seeking behavior. In this review we start with a functional overview of the homeostatic and hedonic energy balance circuitries; identifying the salient neural, hormonal and humoral components involved. We then delve into how the function of these circuits differs in males and females. Finally, we turn our attention to the ever-emerging roles of nociceptin/orphanin FQ (N/OFQ) and pituitary adenylate cyclase-activating polypeptide (PACAP)—two neuropeptides that have garnered increased recognition for their regulatory impact in energy homeostasis—to further probe how the imposed regulation of energy balance circuitry by these peptides is affected by sex and altered under positive (e.g., obesity) and negative (e.g., fasting) energy balance states. It is hoped that this work will impart a newfound appreciation for the intricate regulatory processes that govern energy homeostasis, as well as how recent insights into the N/OFQ and PACAP systems can be leveraged in the treatment of conditions ranging from obesity to anorexia.

Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders

“…Recently, the hyperphagic effect of N/OFQ was associated to the inhibition of critical neuronal activity, such as the neurotransmission at synapses involving ARC POMC neurons and steroidogenic factor (SF)-1 neurons in the VMN, particularly in males and under HFD condition (see details in [ 67 , 212 , 213 ]. To note, this anorexigenic neurotransmission is implicated in the modulation of homeostatic energy balance because, if activated, attenuates food intake and improves energy expenditure [ 214 , 215 , 216 , 217 , 218 ]. Remarkably, long exposure to HFD increases also the excitability of ARC N/OFQ neurons [ 219 ], leading to an increased sensitivity of VMN SF-1/ARC POMC synapses to the inhibitory action of N/OFQ and thus to a significant overconsumption [ 213 ].…”

Key features of the genetic architecture and evolution of host-microbe interactions revealed by high-resolution genetic mapping of the mucosa-associated gut microbiome in hybrid mice

“…Thus, GPCRs may be key modulators of communication between the gut microbiota and host. Another interesting group of genes are those responding to nutrient levels (Bmp7, Cd40, Aacs, Gclc, Nmur2, Cyp24a1, Adcyap1, Serpinc1, and Wnt11) (Sethi and Vidal-Puig, 2008;Peier et al, 2009;Townsend et al, 2012;Yi and Bishop, 2015;Shi and Tu, 2015;Toderici et al, 2016;Yasuda et al, 2021;Gastelum et al, 2021;), as gut microbiota affect host nutrient uptake (Chung et al, 2018).…”

Protective Effects of PACAP in a Rat Model of Diabetic Neuropathy

“…PACAP acts through G-protein-coupled receptors: its specific receptor is PAC1, while VPAC1 and VPAC2 receptors bind PACAP and VIP with the same affinity. PACAP has a widespread distribution in the body, with the highest expression levels in the nervous system and endocrine glands, where it acts as a neurotransmitter, neuromodulator, and neurohormone [ 2 , 3 , 4 , 5 , 6 ]. In addition, PACAP and its receptors are widely expressed in peripheral organs [ 1 , 7 , 8 , 9 , 10 ], and the peptide plays different roles in numerous physiological processes in the cardiovascular, respiratory, urogenital, musculoskeletal, and digestive systems [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…PACAP acts through G-protein-coupled receptors: its specific receptor is PAC1, while VPAC1 and VPAC2 receptors bind PACAP and VIP with the same affinity. PACAP has a widespread distribution in the body, with the highest expression levels in the nervous system and endocrine glands, where it acts as a neurotransmitter, neuromodulator, and neurohormone [2][3][4][5][6]. In addition, PACAP and its receptors are widely expressed in peripheral Int.…”