ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially by increasing FGF21 expression. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis under physiological stress by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue. Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis under fed conditions likely in a FGF21-independent manner, in part via increased amino acid uptake and metabolism.

ATF4 Expression in Thermogenic Adipocytes is Required for Cold-Induced Thermogenesis in Mice via FGF21-Independent Mechanisms.

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially via upregulation of FGF21. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis by generating mice selectively lacking either Atf4 ( ATF4 BKO ) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum -fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue (WAT). Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum -fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis by activating amino acid metabolism in BAT in a FGF21-independent manner.

Cordyceps inhibits ceramide biosynthesis and improves insulin resistance and hepatic steatosis.

Ectopic ceramide accumulation in insulin-responsive tissues contributes to the development of obesity and impairs insulin sensitivity. Moreover, pharmacological inhibition of serine palmitoyl transferase (SPT), the first enzyme essential for ceramide biosynthesis using myriocin in rodents reduces body weight and improves insulin sensitivity and associated metabolic indices. Myriocin was originally extracted from fruiting bodies of the fungus Isaria sinclairii and has been found abundant in a number of closely related fungal species such as the Cordyceps. Myriocin is not approved for human use but extracts from Cordyceps are routinely consumed as part of traditional Chinese medication for the treatment of numerous diseases including diabetes. Herein, we screened commercially available extracts of Cordyceps currently being consumed by humans, to identify Cordyceps containing myriocin and test the efficacy of Cordyceps extract containing myriocin in obese mice to improve energy and glucose homeostasis. We demonstrate that commercially available Cordyceps contain variable amounts of myriocin and treatment of mice with a human equivalent dose of Cordyceps extract containing myriocin, reduces ceramide accrual, increases energy expenditure, prevents diet-induced obesity, improves glucose homeostasis and resolves hepatic steatosis. Mechanistically, these beneficial effects were due to increased adipose tissue browning/beiging, improved brown adipose tissue function and hepatic insulin sensitivity as well as alterations in the abundance of gut microbes such as Clostridium and Bilophila. Collectively, our data provide proof-of-principle that myriocin containing Cordyceps extract inhibit ceramide biosynthesis and attenuate metabolic impairments associated with obesity. Moreover, these studies identify commercially available Cordyceps as a readily available supplement to treat obesity and associated metabolic diseases.