Leptin mediates the increase in blood pressure associated with obesity.

Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

Does leptin cause an increase in blood pressure in animals and humans?

PURPOSE OF REVIEW: Cardiovascular diseases (CVDs) are the number one cause of death globally. The risk for the development of CVDs is significantly increased in obesity. Leptin, the product of white adipose tissue, appears to contribute to the development of CVDs in obesity. Here, we discuss the premise that leptin engages the sympathetic nervous system and contributes to elevated blood pressure (BP) developing in obesity. RECENT FINDINGS: The long-term regulation of BP is dependent on the activity of the autonomic nervous system and specifically the sympathetic nervous system. Sympathetic nerve activity is significantly increased in obese rodents and humans. Leptin increases sympathetic nerve activity in rodents and humans; however, leptin only consistently increases BP chronically in rodents. The ability of leptin to increase BP in rodents is via both hypothalamic and extrahypothalamic regions. In leptin-deficient and leptin receptor-deficient humans, leptin appears to be the key reason for decreased systolic BP. However, in other research conducted in humans, chronic administration of leptin does not elevate BP. SUMMARY: Further research into the role of leptin in the development of CVDs, especially in humans, needs to be conducted.

The Physiological Effects of Air Pollution: Particulate Matter, Physiology and Disease.

Nine out of 10 people breathe air that does not meet World Health Organization pollution limits. Air pollutants include gasses and particulate matter and collectively are responsible for ~8 million annual deaths. Particulate matter is the most dangerous form of air pollution, causing inflammatory and oxidative tissue damage. A deeper understanding of the physiological effects of particulate matter is needed for effective disease prevention and treatment. This review will summarize the impact of particulate matter on physiological systems, and where possible will refer to apposite epidemiological and toxicological studies. By discussing a broad cross-section of available data, we hope this review appeals to a wide readership and provides some insight on the impacts of particulate matter on human health.

Determining the Effects of Combined Liraglutide and Phentermine on Metabolic Parameters, Blood Pressure, and Heart Rate in Lean and Obese Male Mice.

Liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, and phentermine, a psychostimulant structurally related to amphetamine, are drugs approved for the treatment of obesity and hyperphagia. There is significant interest in combination use of liraglutide and phentermine for weight loss; however, both drugs have been reported to induce systemic hemodynamic changes, and as such the therapeutic window for this drug combination needs to be determined. To understand their impact on metabolic and cardiovascular physiology, we tested the effects of these drugs alone and in combination for 21 days in lean and obese male mice. The combination of liraglutide and phentermine, at 100 µg/kg/day and 10 mg/kg/day, respectively, produced the largest reduction in body weight in both lean and diet-induced obese (DIO) mice, when compared with both vehicle and monotherapy-treated mice. In lean mice, combination treatment at the aforementioned doses significantly increased heart rate and reduced blood pressure, whereas in DIO mice, combination therapy induced a transient increase in heart rate and decreased blood pressure. These studies demonstrate that in obese mice, the combination of liraglutide and phentermine may reduce body weight but only induce modest improvements in cardiovascular functions. Conversely, in lean mice, the additional weight loss from combination therapy does not improve cardiovascular parameters.

Repeated weight cycling in obese mice causes increased appetite and glucose intolerance.

Obesity is an ongoing global public health problem. For many people dieting is the preferred method of combating elevated body fat. Weight lost during caloric restriction is often soon regained and so a pattern of recurrent dieting develops. Here an individual's food intake fluctuates up and down with intermittent periods of normal eating and restrained eating. The metabolic consequences of 'yoyo dieting' or 'weight cycling' are not well understood. Here we monitor the effects of multiple, repeated dieting periods on body composition and metabolic health in overweight mice. Compared to mice that were continuously fed a high fat diet, the energy expenditure of diet-cycled mice was reduced. This resulted in mice rapidly regaining body weight upon the reintroduction of high fat chow diet subsequent to periods of caloric restriction. Diet cycling also increased the appetite for high fat chow and diminished glucose tolerance. These data demonstrate the detrimental effects of diet cycling upon metabolic health.

Insulin regulates POMC neuronal plasticity to control glucose metabolism.

Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.