The cellular nutrient sensing apparatus detects nutritional depletion and transmits this information to downstream effectors that generate energy from alternate sources. Autophagy is a crucial catabolic pathway that turns over redundant cytoplasmic components in lysosomes to provide energy to the starved cell. Recent studies have described a role for hypothalamic autophagy in the control of food intake and energy balance. Activated autophagy in hypothalamic neurons during starvation mobilized neuron-intrinsic lipids to generate free fatty acids that increased AgRP levels. AgRP neuron-specific inhibition of autophagy decreased fasting-induced increases in AgRP levels and food intake. Deletion of autophagy in AgRP neurons led to constitutive increases in levels of proopiomelanocortin and its active processed product, α-melanocyte stimulating hormone that contributed to reduced adiposity in these rodents. The current manuscript discusses these new findings and raises additional questions that may help understand how hypothalamic autophagy controls food intake and energy balance. These studies may have implications for designing new therapies against obesity and insulin resistance.
Adipose cells are unique in the dynamism of their sizes, a requisite for their main function of storing and releasing lipid. Lipid metabolism is crucial for energy homeostasis. However, the regulation of lipid storage capacity in conditions of energy excess and scarcity is still not clear. It is not technically feasible to monitor every process affecting storage capacity such as recruitment, growth/shrinkage and death of individual adipose cells in real time for a sufficiently long period. However, recent computational approaches have allowed an examination of the detailed dynamics of adipose cells using statistical information in the form of precise measurements of adipose cell-size probability distributions. One interesting finding is that the growth/shrinkage of adipose cells (> 50 μm diameter) under positive/negative energy balance is proportional to the surface area of cells, limiting efficient lipid absorption/release from larger adipose cells. In addition to the physical characteristics of adipose cells, quantitative modeling integrates dynamics of adipose cells, providing the mechanism of cell turnover under normal and drug-treated conditions. Thus, further use of mathematical modeling applied to experimental measurements of adipose cell-size probability distributions in conjunction with physiological measurements of metabolic state may help unravel the intricate network of interactions underlying metabolic syndromes in obesity.
Adipocytes differentiate and function in environments rich in extracellular matrix (ECM) proteins. The phenotypes of genetically modified mice have aided in recognizing the importance of ECM proteins and their modifiers, e.g., proteinases, in the regulation of obesity and metabolism. Most of the molecular mechanisms through which ECM proteins and modifiers regulate adipogenesis or adipocyte function have not been fully defined. Adipose tissue fibrosis may be a factor that links obesity to diabetes or cardiovascular disease risk in conjunction with tissue inflammation. Defining the molecular mechanisms through which the ECM environment regulates adipogenesis and adipocyte function should provide us with a better understanding of the disease link between obesity and diabetes or cardiovascular diseases.
Galectin-12, a member of the galectin family of animal lectins, is preferentially expressed in adipocytes. We recently reported that this galectin is localized on lipid droplets, specialized organelles for fat storage. Galectin-12 regulates lipid degradation (lipolysis) by modulating lipolytic protein kinase A (PKA) signaling. Mice deficient in galectin-12 exhibit enhanced adipocyte lipolysis, increased mitochondria respiration, reduced adiposity and ameliorated insulin resistance associated with weight gain. The results suggest that galectin-12 may be a useful target for treatment of obesity-related metabolic conditions, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Most previously described galectins largely reside in the cytosol, although they can also be induced to become associated with membrane-containing structures. Along with an in-depth characterization of galectin-12, this mini-review comments on this first report of a galectin normally localized specifically in an organelle that performs an important intracellular function. Further studies will help shed light on how this protein regulates cellular homeostasis, especially energy homeostasis, and provide additional insight into the intracellular functions of galectins.
Objective: UCP2 is a mitochondrial membrane transporter expressed in white adipose tissue and involved in regulation of energy balance. In this present study, we examined the depot specific comparison of UCP2 gene expression in different metabolic states, in order to explore the potential role of UCP2 in human obesity and diabetes. We also determined UCP2’s association with adiponectin and insulin resistance with different parameters of the metabolic syndrome.
Methods: Subcutaneous adipose tissue (SAT) and omental adipose tissues (OAT) were obtained from 69 subjects, including 23 non-obese controls, 26 obese and 20 obese T2DM patients. Metabolic syndrome and other clinical features were studied. Adiponectin and UCP2 gene expression was quantitated by Real Time Reverse Transcriptase Polymerase Chain Reaction (RT-PCR).
Results: UCP2 gene expression was significantly reduced in obese and diabetic patients compared with controls. Interestingly, we found that UCP2 gene expression was reduced more in omental fat compared with subcutaneous fat and this effect was observed only in males but not in females. Partial correlation analysis showed significant association with the obesity parameters waist circumference, insulin and HOMA-IR, the lipid parameter triglyceride and the adipokine adiponectin.
Conclusion: Reduced UCP2 gene expression in obese and diabetic patients and its association with obesity parameters and HOMA-IR confirms its role as a candidate gene in the study of obesity and diabetes in our population. Also, its association with triglycerides implicates its role in lipid metabolism. An association between adiponectin and UCP2 gene expression may provide us with an innovative therapeutic strategy to prevent obesity related diseases, like diabetes and CVD.
Adenosine A1 receptor-deficient mice develop a phenotype of insulin resistance and grow fat. Participating pathophysiological pathways are not understood in detail yet, as discussed in our recent manuscript. This commentary further explores possible pathophysiological mechanisms with emphasis on the roles of the adipokines resistin, retinol-binding protein 4, adiponectin and the function of the gastric hormone ghrelin in adenosine mediated central regulation of energy balance. The postulate of an important function of ghrelin/A1AR axis provides a good hypothetical basis for further investigations to clarify the mechanism of A1AR-dependent metabolic homeostasis.
Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. In a recent study we examined the metabolic features of ct-1 null mice and the effects on body composition, glucose and lipid metabolism of acute and chronic administration of recombinant CT-1. Our data revealed that CT-1 is a key regulator of energy metabolism with potential applications in the treatment of obesity and the metabolic syndrome. This commentary discusses the significance of these findings in the context of other key studies in the field of obesity and insulin resistance.
Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulatory cold-defense and, through its metabolic consumption of energy reserves to produce heat, can affect the long-term regulation of adiposity. An orexinergic pathway from the perifornical lateral hypothalamus (PeF/LH) to the rostral raphe pallidus (rRPa) has been demonstrated to increase the gain of the excitatory drives to medullary sympathetic premotor neurons controlling BAT sympathetic outflow and BAT thermogenesis. With this background, we consider neural mechanisms that could underlie orexin’s modulation of the excitability of BAT sympathetic premotor neurons in rRPa and the potential role of altered BAT thermogenesis in pathological conditions associated with the absence of the central orexin system. Overall, these new data enhance our understanding of the role of central orexin in regulating body temperature and energy homeostasis and provide further insight into the neurochemical regulation of BAT thermogenesis and metabolism.