Hypothalamic Inflammation: Marker or Mechanism of Obesity Pathogenesis?

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

“…We used only normal nonobese rodents. Recent studies document hypothalamic inflammation as an important pathophysiological component of obesity in both animals and humans, and such inflammation may lead to reduced sensitivity of ARC to respond to hormonal input (82,83). Liraglutide effectively lowers body weight in nonobese and obese rats, obese pigs, and humans, and exendin-4 has been show to rapidly circumvent hypothalamic inflammation, all together indicating that nonobese rodents may be a suitable model to describe access to key appetite-regulating neurons (74,79,(84)(85)(86)(87).…”

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Taken together, experimental and clinical studies revealed that most obese subjects and animal models of diet-induced obesity are resistant to the adipostatic actions of leptin (21,22,23). However, defining leptin resistance and identifying the mechanisms behind its development have been a matter of intense investigation and discussion (24,25). First, defining leptin resistance simply as a biological phenomenon characterized by the reduced capacity of leptin to inhibit food intake and promote body mass loss may lead to a conceptual misunderstanding.…”

“…For example, the rather common genetic defects of MCR4 do not produce an impairment of leptin signal transduction but results in the impaired feeding response to leptin (26). A similar concept can be employed for all causes of obesity that arise from defects that are downstream to the early elements of the leptin pathway or affect signaling pathways other than the leptin signaling system (25). Nevertheless, it is currently accepted that in most cases of obesity, leptin resistance plays an important mechanistic role (24).…”

“…Fractalkine produced in this context recruits peripheral monocytes to potentiate and perpetuate hypothalamic inflammation (31). An important aspect of diet-induced hypothalamic inflammation is that intracellular serine/ threonine kinases activated in response to inflammatory signals can target and inhibit key proteins of the leptin and insulin signaling systems, therefore establishing a mechanistic link between hypothalamic inflammation and the resistance to adipostatic signals (25).…”

Regulation of Body Weight and Metabolism by Tanycyte-Derived Neurogenesis in Young Adult Mice

“…The hypothalamic ME, in contrast to other hypothalamic regions, lies outside of the blood-brain barrier and is thus directly exposed to circulating toxins and pathogens, as well as nutrients that can lead to cellular injury when in oversupply. Hypothalamic neural injury and inflammation are seen in obese animals and humans (Thaler et al 2012(Thaler et al , 2013Li et al 2012). The increased neurogenesis in adult female ME may serve to replace damaged neurons in this region.…”