Leptin and metabolic control of reproduction

Leptin treatment prevents the effects of fasting on reproductive processes in a variety of species. The mechanisms that underlie these effects have not been elucidated. Progress in this area of research might be facilitated by viewing reproductive processes in relation to mechanisms that maintain fuel homeostasis. Reproduction, food intake, and fuel partitioning can be viewed as homeostatic responses controlled by a sensory system that monitors metabolic signals. These signals are generated by changes in intracellular metabolic fuel availability and oxidation rather than by changes in the amount of body fat or by changes in any aspect of body composition. Leptin might be viewed as either a mediator or as a modulator of the intracellular metabolic signal. Consistent with its purported action as a mediator of the metabolic signal, leptin synthesis and secretion are influenced acutely by changes in metabolic fuel availability, and these changes might lead to changes in reproductive function. The effects of leptin treatment on reproduction are blocked by treatments that inhibit intracellular fuel oxidation. Metabolic signals that inhibit reproduction in leptin-treated animals might act via neural pathways that are independent of leptin's action. Alternatively, both leptin and metabolic inhibitors might interact at the level of intracellular fuel oxidation. In keeping with the possibility that leptin modulates the metabolic signal, leptin treatment increases fuel availability, uptake, and oxidation in particular tissues. Leptin might affect reproduction indirectly by altering fuel oxidation or other peripheral processes such as gastric emptying. Reproductive processes are among the most energetically expensive in the female repertoire. Because leptin increases energy expenditure while simultaneously inhibiting energy intake, it may have limited use as a long-term treatment for infertility.     

Hypothalamic pathways linking energy balance and reproduction

During periods of metabolic stress, animals must channel energy toward survival and away from processes such as reproduction. The reproductive axis, therefore, has the capacity to respond to changing levels of metabolic cues. The cellular and molecular mechanisms that link energy balance and reproduction, as well as the brain sites mediating this function, are still not well understood. This review focuses on the best characterized of the adiposity signals: leptin and insulin. We examine their reproductive role acting on the classic metabolic pathways of the arcuate nucleus, NPY/AgRP and POMC/CART neurons, and the newly identified kisspeptin network. In addition, other hypothalamic nuclei that may play a role in linking metabolic state and reproductive function are discussed. The nature of the interplay between these elements of the metabolic and reproductive systems presents a fascinating puzzle, whose pieces are just beginning to fall into place.     

Neurocircuits integrating hormone and nutrient signaling in control of glucose metabolism

As obesity, diabetes, and associated comorbidities are on a constant rise, large efforts have been put into better understanding the cellular and molecular mechanisms by which nutrients and metabolic signals influence central and peripheral energy regulation. For decades, peripheral organs as a source and a target of such cues have been the focus of study. Their ability to integrate metabolic signals is essential for balanced energy and glucose metabolism. Only recently has the pivotal role of the central nervous system in the control of fuel partitioning been recognized. The rapidly expanding knowledge on the elucidation of molecular mechanisms and neuronal circuits involved is the focus of this review.     

Thyroid hormones, cytokines, physical training and metabolic control.

During the acute training response, peripheral cellular mechanisms are mainly metabolostatic to achieve energy supply. During prolonged training, glycogen deficiency occurs; this is associated with increased expression of local cytokines, and decreased insulin secretion and beta-adrenergic stimulation and lipolysis in adipose tissue which looses energy. This is indicated by decrease of adipocyte hormone leptin, which has inhibitory effects on excitatory hypothalamic neurons. Leptin, insulin, and cytokines such as interleukin 6 (IL-6) contribute to the metabolic error signal to the hypothalamus which result in decrease of hypothalamic release hormones and sympathoadrenergic stimulation. Thyroid stimulating hormone (TSH) is correlated to the metabolic hormones leptin and insulin, and may be used as indicator of metabolic control. Because the hypothalamus integrates various error signals (metabolic, hormonal, sensory afferents, and central stimuli), the pituitary's releasing hormones represent the functional status of an athlete. Long-term overtraining will lead to downregulation of hypothalamic hormonal and sympathoadrenergic responses, catabolism, and fatigue. These changes contribute to myopathy with predominant expression of slow muscle fiber type and inadequacy in performance. Thyroid hormones are closely involved in the training response and metabolic control.     

Energy metabolism and rheumatic diseases: from cell to organism

In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. In recent time many new insights have been gained into the control of the immune response through metabolic signals. Activation of immune cells as well as reduced nutrient supply and hypoxia in inflamed tissues cause stimulation of glycolysis and other cellular metabolic pathways. However, persistent cellular metabolic signals can promote ongoing chronic inflammation and loss of immune tolerance. On the organism level, the neuroendocrine immune response of the hypothalamic-pituitary adrenal axis and sympathetic nervous system, which is meant to overcome a transient inflammatory episode, can lead to metabolic disease sequelae if chronically activated. We conclude that, on cellular and organism levels, a prolonged energy appeal reaction is an important factor of chronic inflammatory disease etiology.     

The hidden function of photosynthesis: a sensing system for environmental conditions that regulates plant acclimation responses

Plants convert light energy from the sun into chemical energy by photosynthesis. Since they are sessile, they have to deal with a wide range of conditions in their immediate environment. Many abiotic and biotic parameters exhibit considerable fluctuations which can have detrimental effects especially on the efficiency of photosynthetic light harvesting. During evolution, plants, therefore, evolved a number of acclimation processes which help them to adapt photosynthesis to such environmental changes. This includes protective mechanisms such as excess energy dissipation and processes supporting energy redistribution, e.g. state transitions or photosystem stoichiometry adjustment. Intriguingly, all these responses are triggered by photosynthesis itself via the interplay of its light reaction and the Calvin–Benson cycle with the residing environmental condition. Thus, besides its primary function in harnessing and converting light energy, photosynthesis acts as a sensing system for environmental changes that controls molecular acclimation responses which adapt the photosynthetic function to the environmental change. Important signalling parameters directly or indirectly affected by the environment are the pH gradient across the thylakoid membrane and the redox states of components of the photosynthetic electron transport chain and/or electron end acceptors coupled to it. Recent advances demonstrate that these signals control post-translational modifications of the photosynthetic protein complexes and also affect plastid and nuclear gene expression machineries as well as metabolic pathways providing a regulatory framework for an integrated response of the plant to the environment at all cellular levels.     

The hidden function of photosynthesis: a sensing system for environmental conditions that regulates plant acclimation responses

Plants convert light energy from the sun into chemical energy by photosynthesis. Since they are sessile, they have to deal with a wide range of conditions in their immediate environment. Many abiotic and biotic parameters exhibit considerable fluctuations which can have detrimental effects especially on the efficiency of photosynthetic light harvesting. During evolution, plants, therefore, evolved a number of acclimation processes which help them to adapt photosynthesis to such environmental changes. This includes protective mechanisms such as excess energy dissipation and processes supporting energy redistribution, e.g. state transitions or photosystem stoichiometry adjustment. Intriguingly, all these responses are triggered by photosynthesis itself via the interplay of its light reaction and the Calvin-Benson cycle with the residing environmental condition. Thus, besides its primary function in harnessing and converting light energy, photosynthesis acts as a sensing system for environmental changes that controls molecular acclimation responses which adapt the photosynthetic function to the environmental change. Important signalling parameters directly or indirectly affected by the environment are the pH gradient across the thylakoid membrane and the redox states of components of the photosynthetic electron transport chain and/or electron end acceptors coupled to it. Recent advances demonstrate that these signals control post-translational modifications of the photosynthetic protein complexes and also affect plastid and nuclear gene expression machineries as well as metabolic pathways providing a regulatory framework for an integrated response of the plant to the environment at all cellular levels.     

Brain–gut–adipose-tissue communication pathways at a glance

One of the ‘side effects’ of our modern lifestyle is a range of metabolic diseases: the incidence of obesity, type 2 diabetes and associated cardiovascular diseases has grown to pandemic proportions. This increase, which shows no sign of reversing course, has occurred despite education and new treatment options, and is largely due to a lack of knowledge about the precise pathology and etiology of metabolic disorders. Accumulating evidence suggests that the communication pathways linking the brain, gut and adipose tissue might be promising intervention points for metabolic disorders. To maintain energy homeostasis, the brain must tightly monitor the peripheral energy state. This monitoring is also extremely important for the brain’s survival, because the brain does not store energy but depends solely on a continuous supply of nutrients from the general circulation. Two major groups of metabolic inputs inform the brain about the peripheral energy state: short-term signals produced by the gut system and long-term signals produced by adipose tissue. After central integration of these inputs, the brain generates neuronal and hormonal outputs to balance energy intake with expenditure.Miscommunication between the gut, brain and adipose tissue, or the degradation of input signals once inside the brain, lead to the brain misunderstanding the peripheral energy state. Under certain circumstances, the brain responds to this miscommunication by increasing energy intake and production, eventually causing metabolic disorders. This poster article overviews current knowledge about communication pathways between the brain, gut and adipose tissue, and discusses potential research directions that might lead to a better understanding of the mechanisms underlying metabolic disorders.     

AMPK in the brain: its roles in energy balance and neuroprotection

Adenosine monophosphate-activated protein kinase (AMPK) senses metabolic stress and integrates diverse physiological signals to restore energy balance. Multiple functions are indicated for AMPK in the CNS. While all neurons sense their own energy status, some integrate neuro-humoral signals to assess organismal energy balance. A variety of disease states may involve AMPK, so determining the underlying mechanisms is important. We review the impact of altered AMPK activity under physiological (hunger, satiety) and pathophysiological (stroke) conditions, as well as therapeutic manipulations of AMPK that may improve energy balance.     

Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis

Autophagy and apoptosis are 2 fundamental biological mechanisms that may cooperate or be antagonistic, although both are involved in deciding the fate of cells in physiological or pathological conditions. These 2 mechanisms coexist simultaneously in cells and share common upstream signals and stimuli. Autophagy and apoptosis play pivotal roles in cancer development. Autophagy plays a key function in maintaining tumor cell survival by providing energy during unfavorable metabolic conditions through its recycling mechanism, and supporting the high energy requirement for metabolism and growth. This review focuses on gastrointestinal stromal tumors and cell death through autophagy and apoptosis, taking into account the involvement of both of these processes in tumor development and growth and as mechanisms of drug resistance. We also focus on the crosstalk between autophagy and apoptosis as an emerging field with major implications for the development of novel therapeutic options.     

Mammalian sirtuins and energy metabolism

Sirtuins are highly conserved NAD+-dependent protein deacetylases and/or ADP-ribosyltransferases that can extend the lifespan of several lower model organisms including yeast, worms and flies. The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response. Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals. This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes.     

Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors.

The activation state of beta-adrenergic receptors (beta-ARs) in vivo is an important determinant of hemodynamic status, cardiac performance, and metabolic rate. In order to achieve homeostasis in vivo, the cellular signals generated by beta-AR activation are integrated with signals from a number of other distinct receptors and signaling pathways. We have utilized genetic knockout models to test directly the role of beta1- and/or beta2-AR expression on these homeostatic control mechanisms. Despite total absence of beta1- and beta2-ARs, the predominant cardiovascular beta-adrenergic subtypes, basal heart rate, blood pressure, and metabolic rate do not differ from wild type controls. However, stimulation of beta-AR function by beta-AR agonists or exercise reveals significant impairments in chronotropic range, vascular reactivity, and metabolic rate. Surprisingly, the blunted chronotropic and metabolic response to exercise seen in beta1/beta2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from single beta1- and beta2-AR knockouts as well as the beta1-/beta2-AR double knock-out suggest that in the mouse, beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR). Compensatory alterations in cardiac muscarinic receptor density and vascular beta3-AR responsiveness are also observed in beta1-/beta2-AR double knockouts. In addition to its ability to define beta-AR subtype-specific functions, this genetic approach is also useful in identifying adaptive alterations that serve to maintain critical physiological setpoints such as heart rate, blood pressure, and metabolic rate when cellular signaling mechanisms are perturbed.     

Regulation of synaptic functions in central nervous system by endocrine hormones and the maintenance of energy homoeostasis

Energy homoeostasis, a co-ordinated balance of food intake and energy expenditure, is regulated by the CNS (central nervous system). The past decade has witnessed significant advances in our understanding of metabolic processes and brain circuitry which responds to a broad range of neural, nutrient and hormonal signals. Accumulating evidence demonstrates altered synaptic plasticity in the CNS in response to hormone signals. Moreover, emerging observations suggest that synaptic plasticity underlies all brain functions, including the physiological regulation of energy homoeostasis, and that impaired synaptic constellation and plasticity may lead to pathological development and conditions. Here, we summarize the current knowledge on the regulation of postsynaptic receptors such as AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid), NMDA (N-methyl-D-aspartate) and GABA (γ-aminobutyric acid) receptors, and the presynaptic components by hormone signals. A detailed understanding of the neurobiological mechanisms by which hormones regulate energy homoeostasis may lead to novel strategies in treating metabolic disorders.