Mechanisms of Hypothalamic Inflammation in Obesity

The hypothalamus is the primary area of the central nervous system (CNS) involved in regulating energy intake and energy expenditure. The arcuate nucleus (ARC) of the mediobasal hypothalamus incorporates signals from adipose tissue and the gastrointestinal tract to communicate nutritional status, energy stores, and hunger/satiety. These peripheral signals include insulin, leptin, and gut hormones such as glucagon-like peptide-1 (GLP-1), the hormone targeted by the new generation of antiobesity medications. The ARC comprises two main sets of neurons, the orexigenic (stimulating food intake) and anorexigenic (inhibiting food intake) neurons that counterbalance each other and that mediate the effects of leptin and insulin. The anorexigenic neurons of the ARC produce proopiomelanocortin (POMC), which is converted to alpha-melanocyte–stimulating hormone (MSH). Alpha MSH acts on the melanocortin-4 receptor (MC4R) to reduce food intake and increase energy expenditure, and can be deficient in some genetic disorders.

Hypothalamic Obesity With Specific Pathology

Obesity associated with hypothalamic dysfunction was initially described in patients with craniopharyngioma. Hypothalamic obesity may also result from brain radiation, infection (eg, tuberculosis), autoimmune disease (eg, sarcoidosis), or traumatic brain injury. Thus, clinicians should suspect a hypothalamic component in patients presenting with obesity plus a history of one of these conditions.

In some patients, a hallmark sign of hypothalamic obesity is extreme hunger. These patients may report feeling hungry within 1-2 hours after eating a meal. Insatiable hunger, however, is not pathognomonic for hypothalamic obesity and occurs in other forms of obesity, some of which have a genetic basis.

Recent advances have linked some genetic causes of obesity to the CNS and the hypothalamus specifically. For example, genetic abnormalities involving the MC4R pathway (eg, POMC deficiency) account for a minority of cases of severe obesity in the United States. Adult patients with severe obesity (body mass index ≥ 40) and a history of obesity before age 10 years should be tested for monogenic forms of obesity, as a subset of these individuals will be eligible for treatment with setmelanotide.

Patients with some genetic forms of obesity (mediated by hypothalamic dysfunction) may present with other signs, symptoms, and/or laboratory abnormalities, including pituitary dysfunction, developmental delay, intellectual deficiency, or more benign findings (eg, skin and hair pigmentation). For example, a patient with early-onset severe obesity and hypothyroidism or hypogonadism may have leptin receptor deficiency or deficiency of proprotein convertase subtilisin/kexin type 1 (an enzyme involved in insulin formation), whereas a patient with early-onset severe obesity plus red or ginger-colored hair (or sometimes with no other unusual clinical features) may have POMC deficiency.

There is no single diagnostic test for hypothalamic obesity; the workup includes a physical examination and laboratory testing to evaluate patients for hypothalamic/pituitary hormone deficiencies. Studies have found that resting metabolic rate (RMR) may be disproportionately low in patients with hypothalamic obesity, but there are no published cutoffs that define abnormally low energy expenditure. RMR testing is typically not covered by insurance.

Treatment Options

Except for setmelanotide for specific MC4R pathway abnormalities, there are no targeted treatments for patients with hypothalamic obesity. Patients should therefore be treated symptomatically. Medications approved for treatment of obesity (eg, the GLP-1 receptor agonists liraglutide and semaglutide) have shown some benefit.

One systematic review reported that for patients with hypothalamic obesity caused by craniopharyngioma, weight losses with bariatric surgery were less than what is typically seen with surgery, and a greater risk for weight regain was reported. In patients with genetic disorders that cause hypothalamic obesity and intellectual dysfunction, food may need to be restricted by caregivers in addition to pharmacologic or surgical treatment. Patients suspected of having obesity of hypothalamic origin should be seen by a board-certified obesity medicine specialist and/or an endocrinologist to have a full evaluation and discussion of treatment options.

Most Obesity Probably Has a Hypothalamic Component

In recent years, research has suggested that chronic inflammation in the hypothalamus may contribute to weight gain and insulin resistance. This microscopic inflammation has been referred to as hypothalamic inflammation or gliosis. The inflammatory cascade that occurs in the CNS involves a complex interaction between multiple cell types. Evidence from animal studies indicates that a high-fat diet can induce hypothalamic inflammation, even before weight gain has occurred, and that diet — rather than weight per se — is the inciting factor that initiates the inflammatory process. Specifically, the consumption of saturated fatty acids or polyunsaturated fatty acids, respectively, can induce or mitigate hypothalamic inflammation. Some research has shown that diets high in processed carbohydrates (eg, fructose) also can initiate the cascade of hypothalamic inflammation. Once inflammation in the hypothalamus has been established, insulin and leptin resistance follow, which would be expected to increase adiposity and diabetes risk.

As with classic hypothalamic obesity, there are no tests in clinical care that can define hypothalamic inflammation or gliosis. Research studies have linked two radiologic findings on brain MRI  to hypothalamic gliosis: T2 signal hyperintensity of the mediobasal hypothalamus, relative to the amygdala and putamen; and increased T2 relaxation time of the mediobasal hypothalamus. These findings are based on quantitative MRI, which is a research tool and thus not available in clinical practice. One study found that markers of hypothalamic gliosis improved 9 months after bariatric surgery, supporting a possible role of hypothalamic inflammation in the pathogenesis of obesity and insulin resistance.

There is currently no direct evidence in human studies demonstrating subclinical injury or inflammation in the hypothalamus as a primary cause of obesity. Findings to date suggest a bidirectional relationship — ie, dietary patterns causing weight gain and hypothalamic inflammation that lead to further increases in appetite and reductions in energy expenditure. Hypothalamic inflammation appears to be one of several mechanisms, such as adaptive thermogenesis, by which the human body tends toward a higher body weight over time.

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